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Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans
Abstract
The effect of short-term aerobic exercise and a following ramp incremental cycle ergometry to exhaustion on the acute response of the serum concentrations of brain derived neurotrophic factor (BDNF) and cortisol (COR) was examined in 8 healthy male athletes. Venous and capillary blood samples were drawn at rest, immediately after a 10 min warm-up period with aerobic exercise and after a ramp test to exhaustion, as well as 3, 6, 10 and 15 min post exercise. Capillary blood lactate (LA) concentration and blood gases as well as serum BDNF and COR concentrations did not change during the warm-up period. LA was increased (p<0.05) at the end of the ramp test and during recovery period while bicarbonate concentration, carbon dioxide pressure, pH and base excess were decreased (p<0.05) during this period. Serum BDNF was increased at the point of exhaustion (p<0.05) while no significant differences were found between values at rest and those during recovery period. At 10 and 15 min post incremental exercise, COR concentrations were increased (p<0.05) compared to rest. The present study is the first to demonstrate in humans that in contrast to short duration aerobic exercise immediately after a following short duration high-intensity exercise to exhaustion, there is a transient augmentation of serum BDNF concentration. Short-term response of serum BDNF and COR concentrations differs as BDNF returns to baseline level faster than COR.
... Five studies investigated the effect of moderate aerobic exercise (Tang et al., 2007;Winter et al., 2007;Rojas Vega et al., 2008;Zoladz et al., 2008;Strohle et al., 2010). Two of them investigated the effects of aerobic exercise by employing both moderate and high-intensity workloads (Zoladz et al., 2008;Meyer et al., 2016), whereas six studies concentrated on the effects of high-intensity aerobic exercise only (Rojas Vega et al., 2006;Gustafsson et al., 2009;Goekint et al., 2010b;Laske et al., 2010;Saucedo Marquez et al., 2015;Ross et al., 2019;Murawska-Ciałowicz et al., 2021). Only one study investigated the combined effect of low, moderate and high intensity exercise (Meyer et al., 2016). ...
... Saucedo Marquez et al. (2015) found that higher intensity exercise was slightly more effective vs continuous exercise in elevating serum BDNF concentrations whereas Ross et al. (2019) compared highintensity to low-intensity, finding that only high-intensity exercise produced significant increases in BDNF. Although, studies have found increased BDNF with high intensity exercise (e.g., Rojas Vega et al., 2006;Ferris et al., 2007;Goekint et al., 2008;Gustafsson et al., 2009;Laske et al., 2010;Griffin et al., 2011;Heyman et al., 2012) other studies within this review have shown that moderate intensity exercise can also significantly increase BDNF concentrations following acute exercise (e.g., Schulz et al., 2004;Tang et al., 2007;Goekint et al., 2008;Rojas Vega et al., 2008;Gustafsson et al., 2009). Ross et al. (2019) confirmed the linear relationship between cortisol levels and BDNF following exercise. ...
... An interesting finding was that serum BDNF concentration in the study of Rojas Vega et al. (2006) was comparatively lower than other studies employing healthy adults, though it should be noted that this study recruited recreational athletes. Studies using well-trained subjects have reported lower resting serum BDNF levels (e.g., Chan et al., 2008), although some studies with well-trained, young cyclists have not observed similar lower concentrations (Goekint et al., 2008). ...
The aim of this review was to explore the relevant neurobiology and the association between peripheral levels of brain-derived neurotrophic factor (BDNF) and acute and short to long-term exercise regimes, as well as its relation to depression and antidepressant treatment. A 20-year literature search was conducted. The screening process resulted in 100 manuscripts. Antidepressants as well as acute exercise, particularly high-intensity, elevates BDNF in healthy humans and clinical populations, as evidenced from aerobic and resistance-based studies. Although exercise is increasingly recognised in the management of depression, acute and short-term exercise studies have failed to establish a relationship between the severity of depression and changes in peripheral BDNF. The latter rapidly returns to baseline, possibly indicating a quick re-uptake by the brain, aiding its neuroplasticity functions. The timescale of administration needed for the antidepressants to stimulate biochemical changes is longer than similar increases with acute exercise.
... 11 BDNF concentration in the serum is upregulated in humans after aerobic exercise, 12 with evidence that higher intensities are associated with increased concentrations of BDNF. 13 Studies in animals show that a single episode of exercise immediately following extinction learning of conditioned fear can consolidate extinction retention. 14 Similarly, in humans aerobic exercise following extinction learning leads to reduced fear on a delayed extinction test. ...
... The trial was approved by the University of New South Wales (UNSW) Human Research Ethics Committee. The protocol was prospectively registered on the Australian New Zealand Clinical Trials Registry, ACTRN12612000185864 (appendix pp [7][8][9][10][11][12][13][14]. No changes were made to the trial protocol except that the decision was made before first enrolment not to stratify randomisation according to gender. ...
... BDNF is strongly implicated in extinction learning; 6 therefore, increasing BDNF concentration via brief exercise following exposure therapy might lead to greater maintenance of PTSD reduction. Aerobic exercise can also promote activation of glucocorticoids and noradrenaline (which might be modulated by other medications), 13 and these hormones might also be implicated in the treatment response. We emphasise that other mechanisms might also be responsible for our findings, such as the release of physical tension, including that which could have been related to the exposure, increased self-efficacy or sense of control, or increased emotional regulation resulting from aerobic exercise. ...
Background
Although exposure therapy is central in most front-line psychotherapies of post-traumatic stress disorder (PTSD), many patients do not respond to this treatment. We aimed to investigate the effects of brief aerobic exercise on the efficacy of exposure therapy in reducing the severity of PTSD.
Methods
We did a single-blind, parallel, randomised controlled trial in Sydney, NSW, Australia. We included adults (aged ≥18 years) with clinician-diagnosed PTSD. We excluded participants aged 70 years or older, with imminent suicidal risk (reporting suicidal plan), presence of psychosis or substance dependence, history of moderate-to-severe traumatic brain injury, or presence of a physical disorder or impairment that might be exacerbated by aerobic exercise (eg, back pain). We randomly assigned participants (1:1) to nine 90-min weekly sessions of exposure therapy for PTSD with 10 min aerobic exercise or to the control group of exposure therapy with 10 min passive stretching. The primary outcome was PTSD severity measured by the clinician-administered PTSD scale 2 (CAPS-2), independently assessed at baseline, 1 week after treatment, and 6 months after treatment (primary outcome timepoint).
Findings
Between Dec 12, 2012, and July 25, 2018, we enrolled 130 participants with PTSD, with 65 (50%) participants randomly assigned to exposure therapy with exercise and 65 (50%) to exposure therapy with passive stretching, including 79 (61%) women and 51 (39%) men, with a mean age of 39·1 years (SD 14·4; range 18–69). 99 (76%) participants were White, 14 (11%) were Asian, and 17 (13%) were listed as other. At the 6-month follow-up assessment, participants in the exposure therapy with exercise group showed greater reductions in CAPS-2 scores relative to those in the exposure therapy with stretching group (mean difference 12·1 [95% CI 2·4–21·8]; p=0·023), which resulted in a moderate effect size of 0·6 (0·1–1·1). No adverse events associated with the intervention were reported. The trial was prospectively registered on the Australian and New Zealand Clinical Trials Registry, ACTRN12612000185864.
Interpretation
Brief aerobic exercise has the potential to augment long-term gains of exposure therapy for PTSD, which accords with evidence from studies in animals and humans on the role of exercise in modulating the extinction learning processes. This strategy might offer a simple and affordable means to augment treatment gains for exposure therapy in people with PTSD.
Funding
Australian National Health and Medical Research Council.
... BDNF is also known to be involved in the improvement of cognitive functions and the regeneration of the central nervous system, and myokines are also attracting attention as therapeutic targets for neurodegenerative disease. However, it has been reported that the expression of myokines differs with the amount and duration of intensive exercise (Nofuji et al. 2008) and that the expression of myokines is almost the same in low-intensity exercise (Rojas Vega et al. 2006). Communicated by Michael I Lindinger. ...
... Importantly, BDNF levels peaked at 20 min after stimulation of the entire lower limbs. Several studies have reported on the effects of acute exercise on blood BDNF levels (Gold et al. 2003;Rojas Vega et al. 2006;Tang et al. 2008;Castellano and White 2008). There is agreement that acute exercise of moderate or high intensity temporarily increases serum BDNF, which returns to resting levels immediately after cessation of exercise. ...
... There is agreement that acute exercise of moderate or high intensity temporarily increases serum BDNF, which returns to resting levels immediately after cessation of exercise. For serial changes in serum BDNF after exercise, it has been reported that it is observed up to 3 h after cessation of exercise and immediately recovers to the resting level after cessation (Rojas Vega et al. 2006;Tang et al. 2008;Castellano and White 2008). Based on these findings, we found that BDNF expression by EMS is maintained in the blood for a longer time than BDNF expression by voluntary exercise. ...
Purpose
Electrical muscle stimulation (EMS) is known to be effective at stimulating brain-derived neurotrophic factor (BDNF) levels, but the relationship between the volume of muscle stimulated and BDNF levels is not clear. The purpose of this study was to quantify BDNF as a function of muscle volume stimulated in young adults.
Methods
Twelve young adults (male, n = 9, age = 27.3 ± 5.5 years) were enrolled in this study. Participants completed three testing conditions in randomized order: 23 min of maximum tolerated bilateral stimulation of (1) the quadriceps muscle or (2) the musculature of the entire lower limbs and (3) control testing and retesting after 23 min without an intervention. Blood samples were collected before, immediately after, 20 min after, and 40 min after the intervention when EMS was applied to the thighs or the entire lower limb conditions. Serum obtained from blood collection was used for BDNF analysis.
Results
The delta value of BDNF for the test and retest in the control condition was − 42.1 ± 73.8 pg/mL, and there was no significant difference between the test and retest BDNF. Compared to stimulation of the quadriceps muscle, stimulation of the entire lower limbs produced significantly higher BDNF at 20 min post-treatment than those at pre-treatment or 40 min post-treatment, and BDNF was also significantly higher immediately post-treatment than those at pre-treatment. Only stimulation of the quadriceps muscle did not induce a significant change between pre- and post-treatment.
Conclusion
Our findings suggest that the volume of muscle stimulation is important for increased BDNF.
... During exercise, the synthesis and release of neurotransmitters and neurotrophic factors, as well as the transport of nutrients from the peripheral blood through the blood-brain barrier into the brain, take time (Matta Mello Portugal et al. 2013;Rojas Vega et al. 2006). As the availability of brain glucose and dopamine increases over the course of an exercise session, this enhances the overall activity level of the brain. ...
... However, these effects are ephemeral, as indicated by a decrease in prefrontal cortex oxygenation shortly after exercise cessation (Fumoto et al. 2010). Additionally, while aerobic exercise elevates brain-derived neurotrophic factor (BDNF), crucial for emotional health (Ballesio et al. 2023), this increase is not sustained post-exercise, with levels returning to baseline within 15 min (Rojas Vega et al. 2006). Studies focusing on acute aerobic exercise generally measure emotional regulation performance immediately after the exercise intervention. ...
Aerobic exercise improves the three stages of emotion regulation: perception, valuation and action. It reduces the perception of negative emotions, encourages individuals to reinterpret emotional situations in a positive or non-emotional manner, and enhances control over emotion expression behaviours. These effects are generated via increased prefrontal cortex activation, the strengthening of functional connections between the amygdala and several other brain regions, and the enhancement of the plasticity of key emotion regulation pathways and nodes, such as the uncinate fasciculus. The effect of aerobic exercise on emotion regulation is influenced by the exercise intensity and duration, and by individuals’ exercise experience. Future research may explore the key neural basis of aerobic exercise’s promotion of emotion regulation.
... Over the past three decades, it has garnered significant attention from clinicians and researchers due to its essential role in physiological brain functions, encompassing neurogenesis, synaptic plasticity, learning, and memory abilities (Egan et al., 2003;Hall et al., 2000;Kowiański et al., 2018;Lommatzsch et al., 2005;McAllister et al., 1999). BDNF levels can be influenced by factors, such as age, sex, body mass index (BMI), and exercise (Huang et al., 2014;Jasim, Ghafouri, Gerdle, et al., 2020;Lommatzsch et al., 2005;Okuno et al., 2011;Rojas Vega et al., 2006;Szuhany et al., 2015). ...
... Studies using standardized psychosocial stressors have reported increased serum BDNF levels in healthy participants (Hermann et al., 2021;Linz et al., 2019;Meng et al., 2011). Exercise-induced acute stress also elevates BDNF in serum and plasma (Huang et al., 2014;Rojas Vega et al., 2006;Szuhany et al., 2015). Our previous study found a negative correlation between plasma BDNF and psychological job stress, suggesting a decrease in plasma BDNF due to job stress (Okuno et al., 2011). ...
Introduction
Previous studies have suggested association between brain‐derived neurotrophic factor (BDNF) and the stress level of workers. However, no studies have investigated the potential of salivary mature BDNF (mBDNF) level as a noninvasive biomarker for psychological distress. This study aimed to explore the reliability of salivary mBDNF as a biomarker for psychological distress in healthcare workers. Furthermore, we examined the relationship between salivary and plasma mBDNF levels and their correlation with age, sex, body mass index (BMI), and exercise habits.
Methods
Fifty‐one healthy healthcare workers (26 men) from the University of Occupational and Environmental Health, Japan, participated in this study. In this cross‐sectional study, participants provided demographic information. Psychological distress was assessed using the Kessler 6 (K6). Saliva and blood samples were collected, and mBDNF was measured by ELISA. Spearman's rank correlation coefficient was performed to analyze the relationship between mBDNF (saliva and plasma) and K6. Statistical analyses were conducted using Stata 17.0, and a significance level of p < .05 was applied.
Results
The median K6 score was 1 (interquartile range [IQR]: 0–3). The median (IQR) salivary mBDNF was 1.36 (1.12–1.96) pg/mL, whereas the mean (standard deviation) plasma mBDNF was 1261.11 (242.98) pg/mL. No correlation was observed between salivary and plasma mBDNF concentrations or with the K6 score. Additionally, there were no associations between salivary or plasma mBDNF concentrations and age, sex, or exercise habits. Finally, an association between plasma mBDNF concentration and BMI was found only in univariate analysis.
Conclusion
Our findings indicate that salivary mBDNF can be accurately measured noninvasively in healthcare workers. Within our study sample, salivary mBDNF did not demonstrate any correlation with K6 and plasma mBDNF. Future studies with a larger study sample and a diverse study population consisting of healthy participants and patients with psychiatric disorders are warranted.
... Sample size was estimated from seven previous studies (Cho et al., 2012;Church et al., 2016;Ferris et al., 2007;Rasmussen et al., 2009;Rojas Vega et al., 2006;Schmidt-Kassow et al., 2012;Seifert et al., 2010) examining the BDNF response to acute exercise (three measured plasma, three measured serum, one measured both), in which the average effect size was 1.2 (range 0.8-1.8). Using a conservative effect size of 0.9, the calculated sample size for this study was 12 (power >0.8, significance <0.05). ...
... The correlation between circulating lactate and pBDNF supports this notion; however, lactate concentration is proportional to exercise intensity, and therefore this relationship could be merely coincidental. Several studies have demonstrated an association between exercise-induced lactate elevations and BDNF release (El Hayek et al., 2019;Ferris et al., 2007;Reycraft et al., 2020;Rojas Vega et al., 2006), and lactate infusion at rest also appears to increase peripheral serum-derived BDNF independent of platelet count (Schiffer et al., 2011). Furthermore, the influence of lactate may not be related to the concurrent acidosis, as bicarbonate infusion during intense exercise suppresses acidosis with no effect on increases in circulating lactate or serum-derived BDNF (Rojas Vega, et al., 2012). ...
Intermittent fasting and exercise provide neuroprotection from age‐related cognitive decline. A link between these two seemingly distinct stressors is their capability to steer the brain away from exclusively glucose metabolism. This cerebral substrate switch has been implicated in upregulating brain‐derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, learning and memory, and may underlie some of these neuroprotective effects. We examined the isolated and interactive effects of (1) 20‐h fasting, (2) 90‐min light exercise, and (3) high‐intensity exercise on peripheral venous BDNF in 12 human volunteers. A follow‐up study isolated the influence of cerebrovascular shear stress on circulating BDNF. Fasting for 20 h decreased glucose and increased ketones (P ≤ 0.0157) but had no effect on BDNF (P ≥ 0.4637). Light cycling at 25% of peak oxygen uptake (V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$) increased serum BDNF by 6 ± 8% (independent of being fed or fasted) and was mediated by a 7 ± 6% increase in platelets (P < 0.0001). Plasma BDNF was increased from 336 pg l⁻¹ [46,626] to 390 pg l⁻¹ [127,653] by 90‐min of light cycling (P = 0.0128). Six 40‐s intervals at 100% of V̇O2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ increased plasma and serum BDNF, as well as the BDNF‐per‐platelet ratio 4‐ to 5‐fold more than light exercise did (P ≤ 0.0044). Plasma BDNF was correlated with circulating lactate during the high‐intensity intervals (r = 0.47, P = 0.0057), but not during light exercise (P = 0.7407). Changes in cerebral shear stress – whether occurring naturally during exercise or induced experimentally with inspired CO2 – did not correspond with changes in BDNF (P ≥ 0.2730). BDNF responses to low‐intensity exercise are mediated by increased circulating platelets, and increasing either exercise duration or particularly intensity is required to liberate free BDNF. image
Key points
Intermittent fasting and exercise both have potent neuroprotective effects and an acute upregulation of brain‐derived neurotrophic factor (BDNF) appears to be a common mechanistic link.
Switching the brain's fuel source from glucose to either ketone bodies or lactate, i.e. a cerebral substrate switch, has been shown to promote BDNF production in the rodent brain.
Fasting for 20 h caused a 9‐fold increase in ketone body delivery to the brain but had no effect on any metric of BDNF in peripheral circulation at rest.
Prolonged (90 min) light cycling exercise increased plasma‐ and serum‐derived BDNF irrespective of being fed or fasted and seemed to be independent of changes in cerebral shear stress.
Six minutes of high‐intensity cycling intervals increased every metric of circulating BDNF by 4 to 5 times more than prolonged low‐intensity cycling; the increase in plasma‐derived BDNF was correlated with a 6‐fold increase in circulating lactate irrespective of feeding or fasting.
Compared to 1 day of fasting with or without prolonged light exercise, high‐intensity exercise is a much more efficient means to increase BDNF in circulation.
... We found that both BDNF and TrkB receptors were reduced in the cerebellum at the age of onset of motor coordination deficits. Exercise has been shown to elevate BDNF levels in other brain regions in healthy animals (15)(16)(17)(18) and in mouse models of Alzheimer's disease (14,19,20). We found that chronic voluntary exercise partially restored cerebellar BDNF levels and rescued motor coordination deficits. ...
... Exercise elevates BDNF in the SCA6 84Q/84Q mouse cerebellum Physical exercise can up-regulate BDNF expression in several brain regions (15)(16)(17)(18), including in other neurodegenerative disorders in which BDNF levels are reduced (14,19,20). We wondered whether exercise could increase BDNF levels in the cerebellum of SCA6 84Q/84Q mice. ...
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in postmortem tissue from SCA6 patients. Here, we show that levels of cerebellar BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are reduced at an early disease stage in a mouse model of SCA6 (SCA6 84Q/84Q ). One month of exercise elevated cerebellar BDNF expression and improved ataxia and cerebellar Purkinje cell firing rate deficits. A TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), likewise improved motor coordination and Purkinje cell firing rate and elevated downstream Akt signaling. Prolonged 7,8-DHF administration persistently improved ataxia when treatment commenced near disease onset but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.
... It is well known that the BDNF is a protein sensitive to intense acute training (Saucedo Marquez et al., 2015;Cabral-Santos et al., 2016). Previous studies found that blood lactate may be an important regulatory molecule responsible for inducing BDNF synthesis in the brain (Rojas Vega et al., 2006;El Hayek et al., 2019;Müller et al., 2020). In fact, the blood lactate increased significantly after both HIIT interventions in this study, and the higher blood lactate level was observed following HIIT2 protocol. ...
... In addition, there was sufficient evidence to prove the relationship between cortisol response and exercise intensity. Rojas Vega et al. (2006)found no change in cortisol levels after 10 min moderateintensityexercise. Whereas it significantly increases after 10 min of grade incremental exercise test. VanBruggen et al. (2011) further supported the results mentioned above that serum cortisol significantly increased only after high-intensity exercise. ...
Background: Aerobic exercise could produce a positive effect on the brain by releasing brain-derived neurotrophic factor (BDNF). In untrained healthy humans there seems to be a linear correlation between exercise duration and the positive effect of acute aerobic exercise on brain-derived neurotrophic factor levels. Therefore, we performed two different duration of high-intensity interval training protocols (HIIT), both known to improve cardiovascular fitness, to determine whether then have a similar efficacy in affecting brain-derived neurotrophic factor levels.
Methods: 12 untrained young males (aged 23.7 ± 1.8 years), participated in a randomized controlled cross-over trial. They underwent two different work-to-rest ratio high-intensity interval training protocols: high-intensity interval training 1 (30 min, 15 intervals of 1 min efforts at 85%–90% VO2max with 1 min of active recovery at 50%–60% VO2max) and HIIT2 (30 min, 10 intervals of 2 min efforts at 85%–90% VO2max with 1 min of active recovery at 50%–60% VO2max). Serum cortisol, brain-derived neurotrophic factor were collected at baseline, immediately following intervention, and 30 min into recovery for measurements using a Sandwich ELISA method, blood lactate was measured by using a portable lactate analyzer.
Results: Our results showed that the similar serum brain-derived neurotrophic factor change in both high-intensity interval training protocols, with maximal serum brain-derived neurotrophic factor levels being reached toward the end of intervention. There was no significant change in serum brain-derived neurotrophic factor from baseline after 30 min recovery. We then showed that both high-intensity interval training protocols significantly increase blood lactate and serum cortisol compared with baseline value (high-intensity interval training p < 0.01; high-intensity interval training 2 p < 0.01), with high-intensity interval training 2 reaching higher blood lactate levels than high-intensity interval training 1 ( p = 0.027), but no difference was observed in serum cortisol between both protocols. Moreover, changes in serum brain-derived neurotrophic factor did corelate with change in blood lactate (high-intensity interval training 1 r = 0.577, p < 0.05; high-intensity interval training 2 r = 0.635, p < 0.05), but did not correlate with the change in serum cortisol.
Conclusions: brain-derived neurotrophic factor levels in untrained young men are significantly increased in response to different work-to-rest ratio of high-intensity interval training protocols, and the magnitude of increase is exercise duration independent. Moreover, the higher blood lactate did not raise circulating brain-derived neurotrophic factor. Therefore, given that prolonged exercise causes higher levels of cortisol. We suggest that the 1:1work-to-rest ratio of high-intensity interval training protocol might represent a preferred intervention for promoting brain health.
... Therefore, even in the elderly, there is a need for high-intensity interval exercise and resistance exercise to increase lactate production in relation to the activation of BDNF expression in the hippocampus [19,20], but it is a need to clearly confirm the positive effects [21][22][23]. Although the relationship between increased lactate accumulation and increased blood BDNF concentration as exercise intensity increases [24][25][26] has been widely reported, because the analysis results of the effect of high-intensity exercise are still insufficient, there is a need to analyze the level of lactate production and BDNF expression in the brain and hippocampus according to exercise intensity in elderly people, and the results will be important information for preventing dementia caused by aging. ...
OBJECTIVES This study analyzed the possibility of brain function activation after exercise training of high-intensity interval exercise and moderate-intensity continuous exercise in elderly people.METHODS The subjects of the study were elderly female people aged 65 years or older and were divided into three groups : control group, moderate-intensity continuous training (MICT), and high-intensity interval training (HIIT). Changes of body composition, physical fitness, cognitive function, and cognitive function-related blood variables were compared between before and after 12 weeks of exercise training.RESULTS Body weight, BMI (body mass index), and WHR (waist hip ratio) of body composition in HIIT group decreased significantly (p<0.05) after exercise training, and there was no significant difference in MICT group and the control group. HIIT group significantly (p<0.05) improved in grip strength, muscular endurance, flexibility, balance, cardiorespiratory endurance, and walking ability after exercise training, while MICT group showed significant (p<0.05) improvements only in flexibility, balance, and cardiorespiratory endurance. Regarding blood variables, HIIT group showed significant (p<0.05) differences in BDNF (brain-derived neurotrophic factor), irisin, and β-amyloid after exercise training, MICT group showed significant (p<0.05) differences only in β-amyloid. Cognitive function in HIIT group and MICT group significantly (p<0.05) improved in terms of temporal and spatial orientation, memory, and total scores after exercise training. During the recovery phase after one session of high-intensity interval exercise, blood lactic acid concentration increased significantly.CONCLUSIONS This study was confirmed the possibility of giving that high-intensity interval exercise for the elderly not only produces positive changes in body composition and improves physical fitness and cognitive function, but also frequently stimulates lactate production, helping to activate brain function through changes in BDNF and irisin in the blood.
... Interestingly, upregulated serum BDNF levels in T2DM patients were also reported [33,34]. Such discrepancy is possibly related to physical exercise, obesity, and a balanced diet in T2DM patients [47][48][49][50]. In addition, the serum BDNF levels are increased in T2DM patients who received metformin treatment [3]. ...
Objective
To compare the serum levels of brain-derived neurotrophic factor (BDNF) in type 2 diabetes mellitus (T2DM) patients with healthy controls (HC) and evaluate the BDNF levels in T2DM patients with/without cognitive impairment.
Methods
PubMed, EMBASE, and the Cochrane Library databases were searched for the published English literature on BDNF in T2DM patients from inception to December 2022. The BDNF data in the T2DM and HC groups were extracted, and the study quality was evaluated using the Agency for Healthcare Research and Quality. A meta-analysis of the pooled data was conducted using Review Manager 5.3 and Stata 12.0 software.
Results
A total of 18 English articles fulfilled with inclusion criteria. The standard mean difference of the serum BDNF level was significantly lower in T2DM than that in the HC group (SMD: -2.04, z = 11.19, P <0.001). Besides, T2DM cognitive impairment group had a slightly lower serum BDNF level compared to the non-cognitive impairment group (SMD: -2.59, z = 1.87, P = 0.06).
Conclusion
BDNF might be involved in the neuropathophysiology of cerebral damage in T2DM, especially cognitive impairment in T2DM.
... Moreover, this study examined the effect of traditional judo training and Fitlight training on BDNF saliva levels in élite judo athletes. A growing number of studies have looked at BDNF levels during short-term and long-term exercise both in healthy individuals and in individuals with chronic conditions [51,52]. Results showed that increased blood BDNF may therefore be influenced by both the degree of PA and the training status. ...
... 16,27,117,118 The fact that stronger physiological stimuli can be more effective is also demonstrated by preliminary work which showed that higher training volumes have a more positive effect on psychosis patients than lower ones. 15,16,19,21 Neurobiologically, this could be due to the fact that the regulating effect on the metabolites that are usually altered in psychosis patients, 119,120 such as BDNF, 121 or the (anti-)inflammatory effects of exercise 122 tend to be more distinct with increasing exercise intensity. Although no direct linear relationship can be assumed, our results suggest that a certain minimum intensity of training could be beneficial for psychosis patients, as well as the often postulated minimum duration of the intervention. ...
Background and Hypothesis
Exercise therapy has been shown to be an effective complementary treatment for patients with psychotic disorders. However, the specific impacts of different training modalities remain poorly understood. This article aims to quantitatively review the moderating influence of different exercise modalities, hypothesizing that higher exercise intensity as well as utilization of mindfulness-based exercise (MBE) components, will improve intervention outcomes.
Study Design
PubMed, Web of Science, and PsycINFO were searched from 2010 to March 2022 for randomized controlled trials investigating exercise interventions in patients with psychotic disorders (preregistration: https://doi.org/10.17605/OSF.IO/J8QNS). Outcomes considered were positive/negative symptoms, Positive and Negative Syndrome Scale (PANSS) General Psychopathology/Total scores, depressive symptoms, psychosocial functioning, quality of life, cardiorespiratory fitness, and body mass index. Separate meta-analyses, including moderator analyses, were performed to evaluate the moderating influence of different training modalities.
Study Results
Of 6653 studies, 40 (n = 2111 patients) were included in the meta-analysis. The effects of moderate-intensity exercise exceed low-intensity approaches for PANSS Total scores (P = .02) and depressive symptoms (P = .04). The presence of MBE components was associated with improvements in positive symptoms (P = .04) and PANSS General Psychopathology subscores (P = .04) but also with higher error and between-study heterogeneity. Our analysis also shows improved intervention effects on depression in younger patients (P = .012) and improved psychosocial functioning scores following more frequent sessions (P < .01).
Conclusions
A minimum of moderate intensity should be considered. More frequent training sessions per week also seem to be beneficial. While adding mindfulness elements is promising, it increases heterogeneity and requires caution in terms of generalization.
... K. Chang et al., 2012). For example, while Rojas Vega et al., (2006) suggest that the practice of moderate exercise produces high levels of BDNF, (Hwang et al., 2016) reports that aerobic exercise compared to low-intensity exercise induces positive results in terms of BDNF concentration. Regardless of frequency, (Miyamoto et al., 2018) report that even a single session of chronic moderate-to-intense exercise increases peripheral BDNF levels and improves cognition. ...
... in this regard, studies suggested that blood lactate is involved in the regulation of BDNF blood concentration [93][94][95][96] and associated with greater improvements in executive functions [97,98]. considering that blood lactate is an indicator of exercise intensity, the absence of an acute increase in BDNF s and/or BDNF P in the present study could be due to the low intensity of the used aerobic cycling exercise [99,100] and/or the characteristics of the hypoxic stimulus administered (i.e. the hypoxic dose (e.g. intensity/severity, duration, density, frequency) or method (e.g. ...
Background
Animal and human studies have shown that exposure to hypoxia can increase brain-derived neurotrophic factor (BDNF) protein transcription and reduce systematic inflammatory cytokine response. Therefore, the aim of this study was to investigate the acute and chronic effects of intermittent hypoxic-hyperoxic exposure (IHHE) prior to aerobic exercise on BDNF, interleukin-6 (IL-6), and C-reactive protein (CRP) blood levels in geriatric patients.
Patients and Methods
Twenty-five geriatric patients (83.1 ± 5.0 yrs, 71.1 ± 10.0 kg, 1.8 ± 0.9 m) participated in a placebo-controlled, single-blinded trial and were randomly assigned to either an intervention (IG) or control group (CG) performing an aerobic cycling training (17 sessions, 20 min·session⁻¹, 3 sessions·week⁻¹). Prior to aerobic cycling exercise, the IG was additionally exposed to IHHE for 30 min, whereas the CG received continuous normoxic air. Blood samples were taken immediately before (pre-exercise) and 10 min (post-exercise) after the first session as well as 48 h (post-training) after the last session to determine serum (BDNFS) and plasma BDNF (BDNFP), IL-6, and CRP levels. Intervention effects were analyzed using a 2 x 2 analysis of covariance with repeated measures. Results were interpreted based on effect sizes with a medium effect considered as meaningful (ηp2 ≥ 0.06, d ≥ 0.5).
Results
CRP was moderately higher (d = 0.51) in the CG compared to the IG at baseline. IHHE had no acute effect on BDNFS (ηp2 = 0.01), BDNFP (ηp2 < 0.01), BDNF serum/plasma-ratio (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 = 0.04). After the 6-week intervention, an interaction was found for BDNF serum/plasma-ratio (ηp2 = 0.06) but not for BDNFS (ηp2 = 0.04), BDNFP (ηp2 < 0.01), IL-6 (ηp2 < 0.01), or CRP (ηp2 < 0.01). BDNF serum/plasma-ratio increased from pre-exercise to post-training (d = 0.67) in the CG compared to the IG (d = 0.51). A main effect of time was found for BDNFP (ηp2 = 0.09) but not for BDNFS (ηp2 = 0.02). Within-group post-hoc analyses revealed a training-related reduction in BDNFP in the IG and CG by 46.1% (d = 0.73) and 24.7% (d = 0.57), respectively.
Conclusion
The addition of 30 min IHHE prior to 20 min aerobic cycling seems not to be effective to increase BDNFS and BDNFP or to reduce IL-6 and CRP levels in geriatric patients after a 6-week intervention.
The study was retrospectively registered at drks.de (DRKS-ID: DRKS00025130).
... Moreover, this study examined the effect of traditional judo training and Fitlight training on BDNF saliva levels in élite judo athletes. A growing number of studies have looked at BDNF levels during short-term and long-term exercise both in healthy individuals and in individuals with chronic conditions [51,52]. Results showed that increased blood BDNF may therefore be influenced by both the degree of PA and the training status. ...
... In humans, prior research hypothesized and investigated the role of these neurotrophic factors in exercise-related changes in hippocampal volume [23,32,[54][55][56]; nonetheless, the evidence is still not as converging as in animal models. A caveat to evidence in humans may be that the effects of physical exercise on these neurotrophic factors are possibly fast and transient [48,57] and not detectable by current techniques. ...
Background
There is promising, albeit equivocal, evidence that aerobic exercise training (AET) increases human hippocampal volume. The evidence is unclear, as recent randomized controlled trials (RCTs) have failed to replicate AET’s previously reported favorable effects on hippocampal volume in cognitively unimpaired older individuals. We thus conducted a meta‐analysis of RCTs investigating the effects of AET on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals.
Method
A meta‐analysis of RCTs that delivered AET interventions to older individuals. Inclusion criteria were: 1) cognitively unimpaired, healthy individuals aged ≥ 50; 2) AET intervention delivered for at least four weeks; 3) at least one intervention group and one control group; 4) reported data of the effects of AET on hippocampal volume. Two authors independently screened titles, abstracts, and full texts, performed data extraction and methodological quality assessment of included studies. We performed meta‐analyses with random‐effects robust variance estimation models and meta‐regression analyses to test associations between changes in CRF and hippocampal volume. The primary outcome was changes in hippocampal volume, and the secondary outcome was changes in CRF.
Result
Eight parent trials and one secondary outcome article were eligible. The meta‐analytic summary of 17 effect sizes indicated no significant effects of AET on hippocampal volume (SMD = 0.10, 95%CI ‐0.01 to 0.21, p = 0.073). Meta‐analysis of nine studies and effect sizes showed that AET moderately improved cardiorespiratory fitness (SMD = 0.30, 95%CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not statistically associated with changes in hippocampal volume ( b SE = 0.05, SE = 0.51, p = 0.923). Methodological quality was poor in one, fair in three, good in four, and excellent in one trial.
Conclusion
AET did not show robust effects on hippocampal volume in cognitively unimpaired, healthy older individuals. Since AET significantly improved CRF, a lack of training fidelity is unlikely to explain our findings. The biologically still plausible favorable effects of AET on hippocampal volume in cognitively unimpaired older individuals might be masked by methodological weaknesses and the inclusion of only nine studies. Future studies need to address: the lack of harmonization of hippocampus quantification methods and insufficient power to detect meaningful changes in hippocampal volume across studies.
... In humans, prior research hypothesized and investigated the role of these neurotrophic factors in exercise-related changes in hippocampal volume [23,32,[54][55][56]; nonetheless, the evidence is still not as converging as in animal models. A caveat to evidence in humans may be that the effects of physical exercise on these neurotrophic factors are possibly fast and transient [48,57] and not detectable by current techniques. ...
We conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals. Random-effects robust variance estimation models were used to test differences between AET and controls, while meta-regressions tested associations between CRF and hippocampal volume changes. We included eight studies (N = 554) delivering fully supervised AET for 3 to 12 months (M = 7.8, SD = 4.5) with an average AET volume of 129.85 min/week (SD = 45.5) at moderate-to-vigorous intensity. There were no significant effects of AET on hippocampal volume (SMD = 0.10, 95% CI − 0.01 to 0.21, p = 0.073), but AET moderately improved CRF (SMD = 0.30, 95% CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not associated with changes in hippocampal volume (bSE = 0.05, SE = 0.51, p = 0.923). From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects.
... Exercise has also been shown to be particularly beneficial in neurodegenerative diseases through the promotion of neural mitochondrial activity (Wang and Zheng, 2019). In both rodent models and human trials, physical exercise has been shown to increase neurotrophic factors (e.g., brain-derived neurotrophic factor), which in turn activate cascade pathways that eventually reduce mitochondrial dysfunction and neural excitotoxicity (Gold et al., 2003;Rojas Vega et al., 2006;Lau et al., 2015;Vecchio et al., 2018). These findings have been cited to occur following a range of physical activity, from acute anaerobic to regular aerobic exercise, though meta-analyses suggest that regular aerobic exercise may be more effective in increasing peripheral neurotrophic factor levels, synaptic plasticity, and neurogenesis (Ferris et al., 2007;Rothman et al., 2012;Dinoff et al., 2016). ...
Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells’ mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondria-targeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG.
... In the periphery, acute physical exercise leads to transient increases in both mBDNF concentrations [15][16][17] and cortisol concentrations 18 , but the relationship between the two in this acute phase remains largely unknown 19,20 . Less is known regarding exercise-induced changes in pro-BDNF, with two human studies reporting no change in response to exercise or training in the periphery 21,22 . ...
The interplay between biomarkers of relevance to neuroplasticity and its association with learning and cognitive ability in old age remains poorly understood. The present study investigated acute changes in plasma concentrations of mature brain-derived neurotrophic factor (mBDNF), its precursor protein (pro-BDNF), and cortisol, in response to acute physical exercise and cognitive training interventions, their covariation and role in predicting cognitive performance. Confirmatory results provided no support for mBDNF, pro-BDNF and cortisol co-varying over time, as the acute interventions unfolded, but did confirm a positive association between mBDNF and pro-BDNF at rest. The confirmatory results did not support the hypothesis that mBDNF change following physical exercise were counteracted by temporally coupled changes in cortisol or pro-BDNF, or by cortisol at rest, in its previously demonstrated faciliatory effect on cognitive training outcome. Exploratory results instead provided indications of a general and trait-like cognitive benefit of exhibiting greater mBDNF responsiveness to acute interventions when coupled with lesser cortisol responsiveness, greater pro-BDNF responsiveness, and lower cortisol at rest. As such, the results call for future work to test whether certain biomarker profiles are associated with preserved cognition in old age.
... The use of a target heart rate range not derived from maximal exercise testing (i.e., VO2 max) further ensures efficient clinical translation. The low-to-moderate intensity range employed here may also lessen exercise-induced cortisol [71], which has been shown to negatively impact neuroplasticity [72] and future learning [73]. Confirming if similar priming-induced changes in functional connectivity occur in a stroke population is a next step, but it requires judicious consideration of other personal factors including prior level of function, stroke severity, comorbidities, cognitive level, fitness experience, time since stroke, and medication use [74]. ...
Aerobic exercise and action observation are two clinic-ready modes of neural priming that have the potential to enhance subsequent motor learning. Prior work using transcranial magnetic stimulation to assess priming effects have shown changes in corticospinal excitability involving intra- and interhemispheric circuitry. The objective of this study was to determine outcomes exclusive to priming- how aerobic exercise and action observation priming influence functional connectivity within a sensorimotor neural network using electroencephalography. We hypothesized that both action observation and aerobic exercise priming would alter resting-state coherence measures between dominant primary motor cortex and motor-related areas in alpha (7-12 Hz) and beta (13-30 Hz) frequency bands with effects most apparent in the high beta (20-30 Hz) band. Nine unimpaired individuals (24.8 ± 3 years) completed a repeated-measures cross-over study where they received a single five-minute bout of action observation or moderate-intensity aerobic exercise priming in random order with a one-week washout period. Serial resting-state electroencephalography recordings acquired from 0 to 30 minutes following aerobic and action observation priming revealed increased alpha and beta coherence between leads overlying dominant primary motor cortex and supplementary motor area relative to pre- and immediate post-priming timepoints. Aerobic exercise priming also resulted in enhanced high beta coherence between leads overlying dominant primary motor and parietal cortices. These findings indicate that a brief bout of aerobic- or action observation-based priming modulates functional connectivity with effects most pronounced with aerobic priming. The gradual increases in coherence observed over a 10 to 30-minute post-priming window may guide the pairing of aerobic- or action observation-based priming with subsequent training to optimize learning-related outcomes.
... Nevertheless, it is not clear whether MNs react to BDNF of central or peripheral origin. BDNF levels measured in serum and plasma often increase after endurance exercise in humans 14,[23][24][25][26] and rats 27 . Increased levels of post-training BDNF in the bloodstream may be due to its increased expression either in brain structures 14,15 or skeletal muscles 12,28 . ...
The purpose of this study was to determine whether altered serum and/or muscle concentrations of brain-derived neurotrophic factor (BDNF) can modify the electrophysiological properties of spinal motoneurons (MNs). This study was conducted in wild-type and Bdnf heterozygous knockout rats (HET, SD-BDNF). Rats were divided into four groups: control, knockout, control trained, and knockout trained. The latter two groups underwent moderate-intensity endurance training to increase BDNF levels in serum and/or hindlimb muscles. BDNF and other neurotrophic factors (NFs), including glial cell-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), and neurotrophin-4 (NT-4) were assessed in serum and three hindlimb muscles: the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (Sol). The concentrations of tropomyosin kinase receptor B (Trk-B), interleukin-15 (IL-15), and myoglobin (MYO/MB) were also evaluated in these muscles. The electrophysiological properties of lumbar MNs were studied in vivo using whole-cell current-clamp recordings. Bdnf knockout rats had reduced levels of all studied NFs in serum but not in hindlimb muscles. Interestingly, decreased serum NF levels did not influence the electrophysiological properties of spinal MNs. Additionally, endurance training did not change the serum concentrations of any of the NFs tested but significantly increased BDNF and GDNF levels in the TA and MG muscles in both trained groups. Furthermore, the excitability of fast MNs was reduced in both groups of trained rats. Thus, changes in muscle (but not serum) concentrations of BDNF and GDNF may be critical factors that modify the excitability of spinal MNs after intense physical activity.
... Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family that is generated mainly by the brain [152], but is also secreted by skeletal muscle in response to contractions, and enhances fat oxidation via the activation of the AMPactivated protein kinase [153]. During short-duration aerobic exercise, immediately after a short-duration high-intensity exercise to exhaustion, there is a transient augmentation of serum BDNF concentration in humans [154]. Low levels of BDNF accompanying impaired glucose metabolism in T2D patients have been reported [155]. ...
Insulin resistance onset in skeletal muscle is characterized by the impairment of insulin signaling, which reduces the internalization of glucose, known as glucose uptake, into the cell. Therefore, there is a deficit of intracellular glucose, which is the main source for energy production in the cell. This may compromise cellular viability and functions, leading to pathological dysfunction. Skeletal muscle fibers continuously generate reactive oxygen and nitrogen species (RONS). An excess of RONS produces oxidative distress, which may evoke cellular damage and dysfunction. However, a moderate level of RONS, which is called oxidative eustress, is critical to maintain, modulate and regulate cellular functions through reversible interactions between RONS and the components of cellular signaling pathways that control those functions, such as the facilitation of glucose uptake. The skeletal muscle releases peptides called myokines that may have endocrine and paracrine effects. Some myokines bind to specific receptors in skeletal muscle fibers and might interact with cellular signaling pathways, such as PI3K/Akt and AMPK, and facilitate glucose uptake. In addition, there are cytokines, which are peptides produced by non-skeletal muscle cells, that bind to receptors at the plasma membrane of skeletal muscle cells and interact with the cellular signaling pathways, facilitating glucose uptake. RONS, myokines and cytokines might be acting on the same signaling pathways that facilitate glucose uptake in skeletal muscle. However, the experimental studies are limited and scarce. The aim of this review is to highlight the current knowledge regarding the role of RONS, myokines and cytokines as potential signals that facilitate glucose uptake in skeletal muscle. In addition, we encourage researchers in the field to lead and undertake investigations to uncover the fundamentals of glucose uptake evoked by RONS, myokines, and cytokines.
... Data from previous studies suggest an exercise intensity dependent effect on blood BDNF and VEGF concentrations. Most of these studies used blood lactate to determine the degree of the exercise intensity, suggesting that exercise with higher blood lactate concentrations results in elevated BDNF and plasma concentrations (Vega et al., 2006 The present study was semiexperimental and its design was pre-test and post-test with a control group. The control group was asked to stop training for eight weeks, and repeated phone calls prevented them from participating in the group's training programs. ...
The purpose of the present study was to observe changes in levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), resting metabolic rate (RMR) and maximum oxygen consumption (VO2max) in the gymnast children after an anaerobic gymnastics training program. Thirty beginner gymnasts aged 8-12 years old were randomly assigned to control (n = 15) and experimental (n = 15) groups. The anaerobic gymnastics training was conducted for 8 weeks, 3 times per a week. Each session lasted 45 minutes: 10 min warm-up, 30 min core exercise, and 5 min cool down. The anthropometric and body composition of subjects were measured and growth factors were measured by using human BDNF and VEGF PicoKine™ ELISA Kit and analysis was performed using sandwich enzyme-linked immunosorbent assay (Morland et al.) before and after the intervention, and VO2max, maximum heart rate and RMR were measured using a gas analyzer. At the baseline there were not any significant differences between both groups (p>0.05). But in the post-test, a significant difference was observed for BDNF(p=0.02) and VEGF(p=0.018) values between the two groups. Within-group there was a decrease in the value of the maximum heart rate indicator (P<0.05) and VO2max and BDNF increased significantly after an intervention (P<0.05). In conclusion, the results of the present study suggest that anaerobic gymnastic training increases the level of salivary BDNF and VEGF in children. These types of exercises may also improve cardiorespiratory fitness in children.
... It has been suggested that exercise intensity has an effect on blood BDNF and VEGF levels so high-intensity exercises that produces higher blood lactate levels induce a higher increase in plasma BDNF concentrations (22)(23)(24). To understand the mechanisms that are responsible for increasing the BDNF level, Schiffer et al. (25) used a method called lactate clamp; after the infusion of sodium-lactate, BDNF and lactate increased significantly and reached baseline values at the end of the experiment. ...
Background: Overweight and obesity are prominent threats to pediatric health. The prevalence of childhood obesity has dramatically been increasing worldwide. Objectives: In this study, we analyze the effects of 8-week anaerobic gymnastic training on weight loss and related growth factors in obese children. Methods: In this clinical trial study, 30 obese elementary gymnasts in the age range of 8 to 12 years were randomly divided into control (n=15) and experimental (n=15) groups. The experimental group performed 45 minutes of anaerobic gymnastics training. Anthropometrical and body composition characteristics, maximal oxygen consumption, and the levels of brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor were measured before and after 8 weeks of training. Results: At the baseline, there were no significant differences for any of the dependent variables between the two groups (P≥0.05). After 8 weeks of training, values of weight, waist-hip ratio, body fat percentage, body fat weight, lean body weight, and maximal heart rate decreased significantly (P<0.05) while maximal oxygen consumption and BDNF increased significantly (P<0.05). Conclusions: We concluded that weight loss because of anaerobic gymnastic training may lead to a high serum concentration of BDNF. High BDNF may help in maintaining a reduced weight after intervention for obesity and may increase fat oxidation. The inhibitory effects of weight loss on vascular endothelial growth factor may have abolished the stimulatory effects of exercise and prevented a significant increase in the vascular endothelial growth factor level.
... There is little evidence that BDNF levels return to baseline within in a few minutes (approximately 10-20 min) after the increase induced by exercise [32,33]. In accordance, Germanos and colleagues (2019) found that a water-based exercise protocol evoked short-term effects in Parkinson's Disease patients, specifically altering BDNF levels only after the first session without any delayed response (48 h and 1 month after the intervention). ...
Objective
To evaluate the acute and long-term impact of exergaming (EXE) and conventional therapy (CON) in the peripheral levels of brain-derived neurotrophic factor (BDNF), inflammatory markers (interleukin [IL]-1b, IL-6, IL-8, and tumor necrosis factor-alpha [TNF-α]) and epigenetic mechanisms (global histone H3 and H4 acetylation levels in mononuclear cells) of healthy elderly women. We also evaluated the effect of intervention on cognitive performance in these individuals.
Methods
Twenty-two elderly women were randomly assigned into two groups: EXE (n = 12) and CON (n = 10). Both interventions were performed twice a week for 6 weeks (12 sessions). Blood samples were obtained before intervention, after the first session, and 1 hour after the last session. Cognitive performance was evaluated before and after intervention.
Results
Both EXE and CON interventions ameliorated cognitive performance, improved inflammatory profile, enhanced BDNF levels, and induced histone H4 and H3 hyperacetylation status in elderly women.
Conclusion
Our study demonstrated that the proposed interventions can be considered important strategies capable of promoting cognitive improvement in healthy elderly women. The acetylation status of histones and inflammatory cytokines are possible molecular mechanisms that mediate this beneficial response, being distinctly modulated by acute and long-term exposure.
... factor (VEGF) (Skriver et al., 2014), and cortisol (Vega et al., 2006). These neurophysiological substances have unique actions. ...
The neurophysiological response to exercise on cognition is modulated through chemical pathways which involve several neurotrophic factors and the sex of the individual determines this effect. We examined sex differences in the concentration of neural growth factors (NGF); brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and insulin like growth factor-I (IGF- I) in response to acute high intensity intermittent exercise (HIIE). We also evaluated the relationship of NGF with gonadal hormones before and after the HIIE session. Forty healthy young adults (22 males and 18 females) performed HIIE (4 bouts of 4 minutes at 90–95% HR max with 3min active recovery at 70% HRmax). Venous blood was drawn before and immediately after the exercise session and was analyzed for the concentration of serum BDNF, VEGF, IGF-I, cortisol, estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone, using ELISA method. A significant sex difference (p<0.05) was observed for BDNF concentration in response to HIIE and a significant increase was found in males but not in females. A significant (p<0.005) positive correlation of BDNF with FSH and LH and a significant (p<0.05) negative correlation of BDNF and VEGF with testosterone were found. Other NGFs (VEGF and IGF-I) did not show sex differences in response to HIIE. In conclusion, a single session of HIIE increases the serum concentration of BDNF in males and IGF-I in females and the response of NGF is different in males and females.
... Plasma BDNF concentrations were analyzed by enzyme immunoassay using ELISA kits by Millipore (Temecula, CA, USA) according to the manufacturer's description and the protocol used by a previous study (Rojas Vega et al., 2006). The intensity of light was detected by a photometer (Microplate reader, ThermoFisher, New York, USA) with a 450 nm filter. ...
Regular exercise has been shown to be one of the most important lifestyle influences on improving functional performance, and decreasing morbidity and all-cause mortality among older people. However, although there is some evidence on the effects of aerobic training on oxidative stress, there is little information regarding the effects of multicomponent exercise (dual-task training) and combination of exercise with cognitive stimulation on oxidative stress. In this context, the aim of this study was to verify the effects of a multicomponent exercise program on physical fitness and cognitive function in the elderly with mild cognitive impairment and determine the role of oxidative stress and brain-derived neurotrophic factor (BDNF). At baseline, 37 elderly nursing home residents with mild cognitive impairment were divided into two groups: the control group (CG, n = 12, 81.8 years) and the experimental group (EG, n = 25, 83.2 years). These elderlies followed multicomponent exercise training for 24 weeks, with two sessions per week and 45–50 min per session. The exercises included both aerobic and strength exercises, considering functional movements and light to moderate intensity. Cognitive stimulation comprehended exercises based on word games, puzzles, mathematical calculations, forward and backward counting, computer exercises, exergames, and games on a balanced platform. Physical assessments (weight, height, and body mass index), health and functional parameters (fitness tests: chair stand, arm curls, chair sit-and-reach, eight feet up-and-go, back scratch, 6-min walking, feet together, semi-tandem, and full tandem), lipid profile (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides), measures of lipid peroxidation damage, thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), and BDNF were measured in plasma, based on which analyses were performed before and after the 24 weeks of the multicomponent exercise intervention. The results showed an overall improvement in physical and functional performance. Regarding biochemical measures, multicomponent exercises lead to a significant decrease in oxidative damage. The results indicate that multicomponent exercise training induces benefits in functional capacity and reduces damage due to oxidative stress.
... A large body of research supports a role for circulating neurotrophic factors, notably BDNF, in exercise-induced effects. Nearly 25 years ago, physically active rodents were found to have upregulated BDNF protein expression within brain regions such as the hippocampus, and more recent reports have revealed significant increases in BDNF release, or conversion (proteolytic cleavage of proBDNF into mBDNF) following a single session of exercise (Neeper et al., 1995;Rasmussen et al., 2009;Rojas Vega et al., 2006;Tang et al., 2008). Importantly, compelling evidence implicates BDNF in activity dependent plasticity via the tropomyosin-related kinase B (TrkB) receptor (Guo et al., 2014;Kang and Schuman, 1995a;Lu, 2003;Lu et al., 2005). ...
Following acute exercise, a temporal window exists wherein neuroplasticity is thought to be heightened. Although a number of studies have established that pairing this post-exercise period with motor training enhances learning, the mechanisms through which exercise-induced priming occurs are not well understood. Previously, we characterized a rodent model of acute exercise that generates significant enhancement in glutamatergic receptor phosphorylation as a possible mechanism to explain how exercise-induced priming might occur. However, whether these changes are stimulated by peripheral factors (e.g., glucocorticoids), central effects (e.g., brain-derived neurotrophic factor (BDNF), or a combination of the two remains unclear. Herein, we explored the possible individual and/or cumulative contribution corticosterone (CORT) and BDNF may have on glutamate receptor phosphorylation and synaptic surface expression. Tissue slices from the sensorimotor cortex were prepared and acutely (30 min) incubated with either CORT (200 nM), BDNF (20 ng/mL), or the simultaneous application of CORT and BDNF (CORT+BDNF). Immunoblotting with biotinylated synaptoneurosomes (which provide an enrichment of proteins from the synaptic surface) suggested divergent effects between CORT and BDNF. Acute CORT application enhanced NMDA- (GluN2A, B) and AMPA- (GluA1) receptor phosphorylation, whereas BDNF preferentially increased synaptic surface expression of both NMDA- and AMPA-receptor subunits. The combined effects of CORT+BDNF resulted in a unique subset of signaling patterns that favored phosphorylation in the absence of surface expression. Taken together, these data provide a mechanistic framework for how CORT and BDNF may alter glutamatergic synapses during exercise-induced priming.
... June 2022 | Volume 13 | Article 898603 serum BDNF levels did not change following HIIT. Moreover, Rojas Vega et al. (2006) found that serum BDNF of healthy male athletes elevated immediately following a bout of ramp incremental cycle ergometry, but serum cortisol levels did not change following HIIT. It has been pointed out that BLa is a key factor inducing BDNF synthesis (El Hayek et al., 2019;Müller et al., 2020), however, cortisol is a key factor suppressing BDNF synthesis (Issa et al., 2010;Kino et al., 2010;García-Suárez et al., 2020). ...
Objective: The aim of this study was to investigate the effects of single bouts of high-intensity interval training (HIIT) with different duration on serum brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor-A (VEGF-A) levels and cognitive function in healthy young men.
Methods: Twelve healthy young men were participated in two HIIT treatments (20 min HIIT and 30 min HIIT) in a random order. BDNF, VEGF-A, cortisol, testosterone, blood lactic acid were measured and cognitive function was assessed by Stroop test (CWST) and Digital Span test (DST) before, immediately after, and 30 min after HIIT.
Results: 20 and 30 min HIIT increased BLa (both p < 0.01), cortisol (20 min HIIT: p < 0.05; 30 min HIIT: p < 0.01), and testosterone (both p < 0.05) levels immediately when compared with their baselines. While BLa and cortisol were significantly higher in 30 min HIIT group than in 20 min HIIT group. Moreover, BDNF concentration ( p < 0.01), DST-F ( p < 0.01) and DST-B ( p < 0.05) were increased and response time of Stroop was decreased immediately after HIIT only in 20 min HIIT group. VEGF-A concentration was increased immediately after HIIT in both groups ( p < 0.01), but after 30 min recovery, it was returned to the baseline in the 20 min HIIT group and was lower than the baseline in 30 min HIIT group ( p < 0.05).
Conclusion: Twenty minutes HIIT is more effective than 30 minutes HIIT for promoting serum levels of BDNF and VEGF-A as well as cognitive function in healthy young men.
... In contrast, we found no significant increases in circulating BDNF after acute AE at any intensity. Although the current study did not observe a significant increase in circulating BDNF, our findings align with previous work suggesting circulating BDNF returns to basal levels 30 minutes post AE [63]. It is important to note that transient increases in circulating BDNF after acute AE were not detected in older trained populations [45]. ...
Background:
Cathepsin B (CTSB) and brain derived neurotrophic factor (BDNF) are increased with aerobic exercise (AE) and skeletal muscle has been identified as a potential source of secretion. However, the intensity of AE and the potential for skeletal muscle contributions to circulating CTSB and BDNF have not been fully studied in humans.
Objective:
Determine the effects of AE intensity on circulating and skeletal muscle CTSB and BDNF expression profiles.
Methods:
Young healthy subjects (n = 16) completed treadmill-based AE consisting of VO2max and calorie-matched acute AE sessions at 40%, 65% and 80% VO2max. Fasting serum was obtained before and 30-minutes after each bout of exercise. Skeletal muscle biopsies (vastus lateralis) were taken before, 30-minutes and 3-hours after the 80% bout. Circulating CTSB and BDNF were assayed in serum. CTSB protein, BDNF protein and mRNA expression were measured in skeletal muscle tissue.
Results:
Serum CTSB increased by 20±7% (p = 0.02) and 30±18% (p = 0.04) after 80% and VO2max AE bouts, respectively. Serum BDNF showed a small non-significant increase (6±3%; p = 0.09) after VO2max. In skeletal muscle tissue, proCTSB increased 3 h-post AE (87±26%; p < 0.01) with no change in CTSB gene expression. Mature BDNF protein decreased (31±35%; p = 0.03) while mRNA expression increased (131±41%; p < 0.01) 3 h-post AE. Skeletal muscle fiber typing revealed that type IIa and IIx fibers display greater BDNF expression compared to type I (p = 0.02 and p < 0.01, respectively).
Conclusions:
High intensity AE elicits greater increases in circulating CTSB compared with lower intensities. Skeletal muscle protein and gene expression corroborate the potential role of skeletal muscle in generating and releasing neuroprotective exerkines into the circulation.NEW AND NOTEWORTHY: 1) CTSB is enriched in the circulation in an aerobic exercise intensity dependent manner. 2) Skeletal muscle tissue expresses both message and protein of CTSB and BDNF. 3) BDNF is highly expressed in glycolytic skeletal muscle fibers.
... Another external regulator of dopamine, in addition to serotonin, is brain-derived neurotrophic factor (BDNF). Rojas Vega et al. (2006) reported that serum BDNF transiently increased at the point of exhaustion during incremental exercise in healthy male athletes. In addition, long-term regular aerobic training was reported to increase the serum BDNF concentration at rest and even during 2 days of recovery (Jeon & Ha, 2015). ...
Background:
Physical fitness optimization and injury risk-reducing require extensive monitoring of training loads and athletes' fatigue status. This study aimed to investigate the effect of a 6-month training program on the training-related stress indicators (creatine kinase - CK; cortisol - COR; serotonin - SER; brain-derived neurotrophic factor - BDNF) in youth soccer players.
Methods:
Eighteen players (17.8 ± 0.9 years old, body height 181.6 ± 6.9 cm, training experience 9.7 ± 1.7 years) were blood-tested four times: at the start of the preparation period (T0), immediately following the preparation period (T1), mid-competitive period (T2), and at the end of the competitive period (T3). CK activity as well as concentrations of serum COR, SER and BDNF were determined. Training loads were recorded using a session rating of perceived exertion (sRPE).
Results:
Statistical analyzes revealed significant effects for all biochemical parameters in relation to their time measurements (T0, T1, T2, T3). The statistical analyzes of sRPE and differences of biochemical parameters in their subsequent measurements (T0-T1, T1-T2, T2-T3) also demonstrated significant effects observed for all variables: sRPE (HKW = 13.189 (df = 2); p = 0.00), COR (HKW = 9.261 (df = 2); p = 0.01), CK (HKW = 12.492 (df = 2); p = 0.00), SER (HKW = 7.781 (df = 2); p = 0.02) and BDNF (HKW = 15.160 (df = 2); p < 0.001).
Discussion:
In conclusion, it should be stated that the most demanding training loads applied in the preparation period (highest sRPE values) resulted in a significant increase in all analyzed biochemical training stress indicators. The reduction in the training loads during a competitive period and the addition of recovery training sessions resulted in a systematic decrease in the values of the measured biochemical indicators. The results of the study showed that both subjective and objective markers, including training loads, are useful in monitoring training stress in youth soccer players.
... This may be the reason of more rises in S. BDNF levels. This supports findings of Rojas-Vega et al. 22 who reported that when athletes performed 10 min of warm-up exercises, there was no notable change in the serum BDNF concentration level. However, after subjects performed ramp tests, the level of serum BDNF significantly increased. ...
... Few studies report the specific timing of venous sampling, and most studies appear to take single blood samples immediately post-exercise (Knaepen et al., 2010). Some evidence suggests that BDNF levels may return to baseline within 15-20 min of exercise cessation (Vega et al., 2006;Marquez et al., 2015), thus the timing of the post-exercise blood sample in this study (20 min) may have been a limiting factor in the interpretation of our results. Therefore, future studies should consider obtaining blood samples immediately after exercise and also aim to determine optimal exercise dosing for enhancing BDNF in both sexes. ...
Transcranial magnetic stimulation studies have demonstrated increased cortical facilitation and reduced inhibition following aerobic exercise, even when examining motor regions separate to the exercised muscle group. These changes in brain physiology following exercise may create favorable conditions for adaptive plasticity and motor learning. One candidate mechanism behind these benefits is the increase in brain-derived neurotropic factor (BDNF) observed following exercise, which can be quantified from a venous blood draw. The aim of this study was to investigate changes in motor cortex excitability and inhibition of the upper limb, and circulating BDNF, following high-intensity interval training (HIIT) on a stationary bicycle. Nineteen sedentary adults participated in a randomized crossover design study involving a single bout of high-intensity interval cycling for 20 min or seated rest. Venous blood samples were collected, and transcranial magnetic stimulation (TMS) was used to stimulate the extensor carpi radialis (ECR), where motor evoked potentials (MEP) were recorded pre- and post-condition. Following exercise, there was a significant increase (29.1%, p < 0.001) in corticospinal excitability measured at 120% of resting motor threshold (RMT) and a reduction in short-interval cortical inhibition (SICI quantified as 86.2% increase in the SICI ratio, p = 0.002). There was a non-significant (p = 0.125) 23.6% increase in BDNF levels. Collectively, these results reflect a net reduction in gamma aminobutyric acid (GABA)ergic synaptic transmission and increased glutamatergic facilitation, resulting in increased corticospinal excitability. This study supports the notion that acute high-intensity exercise provides a potent stimulus for inducing cortical neuroplasticity, which may support enhanced motor learning.
... Serum BDNF and serum cortisol were overall greater in the match trial, compared to the control trial, which agrees with previous literature where both are greater in response to moderate intensity exercise (Vega et al., 2006). Studies have shown increases in BDNF following high impact anaerobic work to positively influence learning (Winter et al., 2007) and working memory (Griffin et al., 2011). ...
Despite the known positive effects of acute exercise on cognition, the effects of a competitive team sport match are unknown. In a randomized crossover design, 20 female and 17 male field hockey players (19.7 ± 1.2 years) completed a battery of cognitive tests (Visual Search, Stroop, Corsi Blocks, and Rapid Visual Information Processing) prior to, at half-time, and immediately following a competitive match (or control trial of seated rest); with effect sizes (ES) presented as raw ES from mixed effect models. Blood samples were collected prior to and following the match and control trial, and analyzed for adrenaline, noradrenaline, brain derived neurotrophic factor (BDNF), cathepsin B, and cortisol. The match improved response times for a simple perception task at full-time (ES = –14 ms; P < 0.01) and response times on the complex executive function task improved at half-time (ES = –44 ms; P < 0.01). Working memory declined at full-time on the match (ES = –0.6 blocks; P < 0.01). The change in working memory was negatively correlated with increases in cortisol ( r = –0.314, P = 0.01; medium), as was the change in simple perception response time and the change in noradrenaline concentration ( r = –0.284, P = 0.01; small to medium). This study is the first to highlight the effects a competitive hockey match can have on cognition. These findings have implications for performance optimization, as understanding the influence on specific cognitive domains across a match allows for the investigation into strategies to improve these aspects.
... [8] Exercise-induced activation of the sympathetic nervous system results in increased production and secretion of epinephrine (Epi) and norepinephrine (NE) from the adrenal medulla and postganglionic neurons respectfully at the onset of exercise and continues to rise in an intensity and duration-dependent manner. [9,10] High-intensity exercise leads to increase in plasma cortisol levels, [11] which is apparently required to cope with the higher energy demand. [12] It can be used as a biomarker to understand the level of stress exerted by high-intensity exercise. ...
BACKGROUND: Military training activities are typically challenging and push the soldiers toward their maximum limits of capabilities to improve proficiency in real time situations. In terms of injury prevention, unit performance, and overall morale, the individual's physical capabilities must be in concert to the job demands. Hormones play an important role in regulating various physiological processes including fuel utilization by exercising muscles.
AIMS AND OBJECTIVES: This study was undertaken to quantify the hormonal demand of an intense military training event.
MATERIALS AND METHODS: The study was conducted at a military training center on 25 male healthy soldiers who had completed 11 week training. Venous blood samples were drawn before and immediately after the event.
RESULTS: In hormonal responses, the levels of epinephrine (P < 0.001), norepinephrine (P < 0.01), cortisol (P < 0.001), serotonin (P < 0.01), and aldosterone (P < 0.001) were significantly increased while testosterone (P < 0.001) was found significantly decreased after event. The present study demonstrated that the physical proficiency training activity was highly energy demanding due to significantly increased sympathoadrenergic responses and induced a high level of acute stress due to significant reduction of testosterone. In addition to this, the significantly increased serotonergic responses indicated that the level of fatigue was high during activity.
CONCLUSION: The findings of the present study may be helpful in screening of individuals before inducting into such intense military training activity to minimize the risk of injuries.
Brain-derived neurotrophic factor (BDNF), a key neurotrophin within the brain, by selectively activating the TrkB receptor, exerts multimodal effects on neurodevelopment, synaptic plasticity, cellular integrity and neural network dynamics. In parallel, glucocorticoids (GCs), vital steroid hormones, which are secreted by adrenal glands and rapidly diffused across the mammalian body (including the brain), activate two different groups of intracellular receptors, the mineralocorticoid and the glucocorticoid receptors, modulating a wide range of genomic, epigenomic and postgenomic events, also expressed in the neural tissue and implicated in neurodevelopment, synaptic plasticity, cellular homeostasis, cognitive and emotional processing. Recent research evidences indicate that these two major regulatory systems interact at various levels: they share common intracellular downstream pathways, GCs differentially regulate BDNF expression, under certain conditions BDNF antagonises the GC-induced effects on long-term potentiation, neuritic outgrowth and cellular death, while GCs regulate the intraneuronal transportation and the lysosomal degradation of BDNF. Currently, the BDNF-GC crosstalk features have been mainly studied in neurons, although initial findings show that this crosstalk could be equally important for other brain cell types, such as astrocytes. Elucidating the precise neurobiological significance of BDNF-GC interactions in a tempospatial manner, is crucial for understanding the subtleties of brain function and dysfunction, with implications for neurodegenerative and neuroinflammatory diseases, mood disorders and cognitive enhancement strategies.
چكيده
كه از نظر ساختاري شبيه فاكتور رشد عصبي است، در قسمت هيپوكامپ (BDNF) فاكتور نوروتروفيك مشتق از مغز
بر BDNF توليد مي شود و يكي از فاكتورهايي است كه در دوران سالمندي در اثر فقدان فعاليت كاهش مي يابد. كاهش
حافظه، يادگيري و شناخت، ، جذب غذا و متابوليسم انرژي تأثير مي گذارد و سبب اختلال رفتاري م ي شود؛ با فعاليت
ورزشي مي توان اين كمبود را جبران و حتي از بروز آلزايمر جلوگيري كرد . هدف از اجراي اين پژوهش ، بررسي اثر
سرم در مردان سالمند بود. براي اين منظور 20 مرد سالمند به طور تصادفي در دو BDNF تمرينات پيلاتس بر سطح
64 سال) و ميانگين وزن (گروه ±2/ 65 سال، گروه تجربي 62 ±2/ گروه تجربي و كنترل با ميانگين سني (گروه كنترل 67
71 كيلوگرم) تقسيم شدند. از كلية آزمودني ها 24 ساعت قبل از شروع ±3/ 73 كيلوگرم، گروه تجربي 54 ±3/ كنترل 59
تمرينات و 24 ساعت پس از پايان دورة تمريني، به صورت ناشتا خون گيري به عمل آمد. سپس گروه تجربي به مدت 12
هفته (هر هفته 5 جلسه و هر جلسه به مدت 60 دقيقه) برنامة ورزشي پيلاتس را دريافت كردند. درحالي كه گروه كنترل
همبسته و براي t هيچ مداخل هاي دريافت نكردند و تنها پيگيري شدند. به منظور مقايسة درون گروهي از آزمون آماري
سرم در گروه تجربي در مقايسه با BDNF مستقل استفاده شد. يافته ها نشان داد كه سطوح t مقايسة بين گروهي از
نتايج اين تحقيق نشان مي دهد كه تمرينات پيلاتس به عنوان يك .(P<0/ گروه كنترل به طور معناداري افزايش يافت ( 05
در BDNF سرم مردان سالمند مي شود. بنابراين، با توجه به اينكه BDNF روش ايمن و مؤثر، سبب افزايش سطوح
دوران سالمندي بر اثر بي تحركي كاهش مي يابد، مي توان كمبود آن را با اجراي تمرينات ك مهزينه و ب ي خطر پيلاتس
جبران كرد.
Background:
Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly. Cognitive dysfunction represents a common and challenging non-motor symptom for people with Parkinson's disease. The number of neurotrophic proteins in the brain is critical in neurodegenerative diseases such as Parkinson's. This research aims to compare the effects of two types of exercise, forced and voluntary, on spatial memory and learning and neurochemical factors (CDNF and BDNF).
Methods:
In this research, 60 male rats were randomly divided into six groups (n = 10): the control (CTL) group without exercise, the Parkinson's groups without and with forced (FE) and voluntary (VE) exercises, and the sham groups (with voluntary and forced exercise). The animals in the forced exercise group were placed on the treadmill for four weeks (five days a week). At the same time, voluntary exercise training groups were placed in a special cage equipped with a rotating wheel. At the end of 4 weeks, learning and spatial memory were evaluated with the Morris water maze test. BDNF and CDNF protein levels in the hippocampus were measured by the ELISA method.
Results:
The results showed that although the PD group without exercise was at a significantly lower level than other groups in terms of cognitive function and neurochemical factors, both types of exercise, could improve these problems.
Conclusion:
According to our results, 4 weeks of voluntary and forced exercises were all found to reverse the cognitive impairments of PD rats.
Background:
Acute exercise appears to promote executive function (EF) in children. However, the effect of acute exercise on EF in children with preterm birth (PB) remains unclear.
Objective:
To investigate whether acute moderate-intensity exercise improves EF in children with PB.
Methods:
Twenty child participants with PB (age = 10.95 ± 1.19 years, birth age = 31.71 ± 3.64 weeks) completed exercise and control sessions in a randomized crossover design. In the exercise session, participants completed a 30-minute period of moderate-intensity aerobic exercise. In the control session, participants watched a video for appropriately 30 min. Following each session immediately, inhibitory control, an aspect of EF, was assessed with the Numerical Stroop task.
Results:
Response time (RT) for the Stroop's incongruent condition was shorter after the exercise session than after the control session. However, no differences were observed in RT for the congruent condition. Accuracy rate (ACC) in both congruent and incongruent conditions did not differ between exercise and control session.
Conclusion:
The findings support the beneficial effect of acute exercise on executive function (EF) in children with PB, particularly in terms of improving inhibitory control.
Objective:
To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery.
Setting:
Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community.
Participants:
Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed).
Design:
A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]).
Main outcome measure:
Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample.
Results:
Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT.
Conclusions:
Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent mTBI.
Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training is a potent stimulus for physiological adaptation in many organs. Specifically in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, is underpinned by activation and/or repression of molecular pathways and processes induced in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and post-transcriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and post-transcriptional regulation, and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.
Obesity has been linked to lower cognitive function, while exercise is known to be beneficial in enhancing the cognitive function. Exercise is also known to increase brain-derived neurotrophic factor (BDNF), as the biological marker of cognitive function. This study aimed to analyse the pattern of serum BDNF levels after acute interval exercise (MIE) versus acute continuous exercise (MCE) in obese adolescent females. A total of 24 obese females were enrolled in this study and given acute interval exercise and acute continuous exercise with moderate intensity. The serum level of BDNF in all samples was quantified using ELISA. Statistical analysis was performed using two-way repeated measures ANOVA, and LSD post-hoc test with a 5% significance level. The results revealed pre-exercise mean serum BDNF levels of 254.17±86.90 pg/ml (Control), 263.21±79.82 pg/ml (MIE) and 266.01±33.29 pg/ml (MCE) (P=0.948). The mean serum BDNF levels at 10 min post-exercise were 248.84±44.42 pg/ml (Control), 397.00±31.36 pg/ml (MIE), and 582.82±79.24 pg/ml (MCE) (P=0.000). The mean serum BDNF levels at 6 h post-exercise were 250.05±70.44 pg/ml (Control), 344.50±68.84 pg/ml (MIE), and 364.42±100.87 pg/ml (MCE) (P=0.029). The mean serum BDNF levels at 24 h post-exercise were 244.20±48.55 pg/ml (Control), 252.49±89.11 pg/ml (MIE), and 250.99±65.86 pg/ml (MCE) (P=0.986). It was concluded that serum BDNF in obese adolescent females increased but transiently. Serum BDNF levels increased by acute exercise in both MIE and MCE at 10 min and 6 h post-exercise. However, serum BDNF level at 24 h post-exercise decreased close to the pre-exercise serum BDNF level in all groups. Further research is needed studying the effect of chronic exercise on the kinetics of serum BDNF levels in obese adolescent females.
Despite advances in diagnostic tools and therapeutic options, chronic kidney disease (CKD) is still a global health problem associated with increased morbidity and mortality. Insulin resistance, muscle wasting, malnutrition and chronic inflammation are highly prevalent in CKD patients. Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor-related family and with its receptor tropomyosin-related kinase receptor B impacts cell differentiation, synaptic connectivity and plasticity of the brain. BDNF is well studied in various populations especially in the area of neurology and psychiatry. Recently, there is also an acceleration of BDNF research in CKD and accumulating evidence suggests that BDNF may be a potential prognostic marker in CKD patients. Specifically, studies have shown that BDNF is associated with insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. However, the data regarding BDNF in CKD is only in its first steps and various issues must be highlighted in upcoming studies. In this review, we have summarized the findings regarding BDNF and its relationship between insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. We also mentioned controversies and possible causes for diverse findings and suggest perspectives in the context of BDNF and CKD.
Problem statement: An increase in exercise intensity enhances the immune system. However, concentrations of cortisol and cytokine responses as acute effects of different exercise intensities need to be comprehensively elucidated. The purpose of this study was to examine the effects of different exercise intensities on concentrations of salivary cortisol and interleukin-6, a proinflammatory cytokine, at four distinct time points. Research Methods: Forty-five participants were classified into three groups (15 participants/group): one control group and two groups undergoing aerobic exercise at 65-80% maximum heart rate and >80% maximum heart rate, respectively. Saliva samples were collected from each participant at 0, 45, 60, and 90 min to measure cortisol and interleukin-6 levels using enzyme-linked immunosorbent assay kits. Results: Salivary cortisol levels at 60 min after exercise significantly differed between the aerobic exercise at 65-80% maximum heart rate and control groups (P = 0.024). Compared with the control group, aerobic exercise in the 65-80% and >80% maximum heart rate showed significantly different effects on altered salivary interleukin-6 levels at 45 and 60 min after exercise (P = 0.004 and P = 0.016, respectively). At 60 min, the concentration of salivary interleukin-6 was significantly higher in the aerobic exercise at 65-80% maximum heart rate than in the ˃80% maximum heart rate group (P = 0.049). Conclusion: Our findings revealed that different intensities of acute aerobic exercise might induce high levels of salivary cortisol and interleukin 6. It would be a beneficial tool for healthy individuals as they strive to rate the work intensity of aerobic exercise.
The risk of dementia increases with age. To mitigate this risk, we examined the effect of a square-stepping exercise (SSE) program on fall-related fitness and brain-derived neurotrophic factor (BDNF) levels. Twenty older adults in Korea were randomly assigned to either the experimental or control group (each group n = 10). Participants performed SSE for 70 min per session, twice a week, for 12 weeks with a certified instructor. The average age of the participants was 74.80 ± 6.763 years in the exercise group and 72.50 ± 6.519 years in the control group. The experiment group showed significant improvement (p < 0.01) in the lower muscle strength post-intervention. The paired t-test revealed a significant improvement (p < 0.01) in the experimental group and a significant difference in the interaction effect (p < 0.01) in the BDNF levels. There was a significant improvement (p < 0.05) in the BDNF levels in the experimental group and a significant decrease (p < 0.05) in the control group. The SSE program had a positive effect on fall-related fitness and BDNF levels.
Neurodegenerative diseases, such as Alzheimer's disease (AD), are becoming more common in aging our society. One specific neuropathological hallmark of this disease is excessive accumulation of amyloid-β (Aβ) peptides, which can aggregate to form the plaques commonly associated with this disease. These plaques are often observed well before clinical diagnosis of AD. At the cellular level, both production and aggregation of Aβ peptides in the brain is detrimental to neuronal cell production, survival, and function, as well as often resulting in neuronal dysfunction and death. Exercise and physical activity have been shown to improve overall health, including brain health, and in the last several years there has been evidence to support that exercise may be able to regulate Aβ peptide production in the brain. Exercise promotes the release of a wide array of signaling mediators from various metabolically active tissues and organs in the body. These exercise-induced signaling mediators could be the driving force behind some of the beneficial effects observed in brain with exercise. This review will aim to discuss potential exercise-induced signaling mediators with the capacity to influence various proteins involved in the formation of Aβ peptide production in the brain.
Purpose The purpose of this study was to investigate the effects of regular vigorous- and moderate-intensity aerobic exercise on serum brain-derived neurotrophic factor (BDNF) level, aging- and lifestyle disease-related blood components in middle-aged women. Methods The participants were recruited from a total of 19 physically healthy people aged 50-59 years, and were randomly divided into vigorous-intensity aerobic exercise (VIAE, n = 10) and moderate-intensity aerobic exercise (MIAE, n = 9) group. The participants were performed vigorous- and moderate-intensity aerobic exercise three times a week for eight weeks, and body composition measurement, graded exercise test, blood collection were performed before and after. Results Mean exercise time was significantly longer in the MIAE group than in the VIAE group. The V̇O2max was significantly higher in the VIAE group than in the MIAE group. Body weight, BMI, and body fat percentage were significantly lower than pre both groups. The BDNF concentration was significantly higher in the VIAE group than in the MIAE group. The dehydroepiandrosterone sulfate (DHEA-s) and insulin-like growth factor-1 (IGF-1) concentration were significantly higher than pre both groups. The free fatty acid and triglyceride concentrations were significantly lower than pre both groups, and HDL-C concentrations were significantly higher than pre both groups. Conclusions Vigorous-intensity aerobic exercise not only increases maximal oxygen uptake and blood BDNF level in middle-aged women, but also induces positive changes in aging-related hormones and lifestyle-related blood variables.
Chronic stress produces structural changes and neuronal damage especially in the hippocampus. Because neurotrophic factors affect neuron survival, we questioned whether they might be relevant to the heightened vulnerability of hippocampal neurons following stress. To begin investigating this possibility, we examined the effects of immobilization stress (2 hr/d) on the expression of neurotrophic factors in rat brains using in situ hybridization. We found that single or repeated immobilization markedly reduced brain-derived neurotrophic factor (BDNF) mRNA levels in the dentate gyrus and hippocampus. In contrast, NT-3 mRNA levels were increased in the dentate gyrus and hippocampus in response to repeated but not acute stress. Stress did not affect the expression of neurotrophin-4, or tyrosine receptor kinases (trkB or C). Corticosterone negative feedback may have contributed in part to the stress-induced decreases in BDNF mRNA levels, but stress still decreased BDNF in the dentate gyrus in adrenalectomized rats suggesting that additional components of the stress response must also contribute to the observed changes in BDNF. However, corticosterone-mediated increases in NT-3 mRNA expression appeared to be primarily responsible for the effects of stress on NT-3. These findings demonstrate that BDNF and NT-3 are stress-responsive genes and raise the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.
The hippocampus is important for the acquisition of new memories. It is also one of the few regions in the adult mammalian brain that can generate new nerve cells. The authors tested the hypothesis that voluntary exercise increases neurogenesis and enhances spatial learning in mice selectively bred for high levels of wheel running (S mice). Female S mice and outbred control (C) mice were housed with and without running wheels for 40 days. 5-Bromodeoxyuridine was used to label dividing cells. The Morris water maze was used to measure spatial learning. C runners showed a strong positive correlation between running distance and new cell number, as well as improved learning. In S runners, neurogenesis increased to high levels that reached a plateau, but no improvement in learning occurred. This is the first evidence that neurogenesis can occur without learning enhancement. The authors propose an alternative function of neurogenesis in the control of motor behavior.
The rat dentate gyrus is unusual among mammalian brain regions in that it shows cell birth well into adulthood. During development, dentate gyrus cell birth is regulated by adrenal steroids. However, it is presently unknown whether cell division in the adult is also mediated by these same factors. In order to determine whether this is the case, we combined adrenalectomy, with or without corticosterone (CORT) replacement, and 3H-thymidine autoradiography, Nissl staining, and immunohistochemistry for the glial cell markers vimentin and glial fibrillary acidic protein (GFAP) as well as for the neuronal marker neuron-specific enolase. Removal of circulating adrenal steroids resulted in a greater density of both GFAP-immunoreactive and vimentin-immunoreactive cells compared to sham-operated animals; CORT replacement prevented increases in both of these cell types. The increase in the density of vimentin-immunoreactive cells probably resulted from an increase in the birth of these cells, as adrenalectomized rats showed greater numbers of 3H-thymidine-labeled vimentin-positive cells compared to sham rats. In contrast, no changes in the number of 3H-thymidine-labeled GFAP-positive cells were observed with adrenalectomy, indicating that the increase in this cell type probably does not involve cell birth. In addition, the density of 3H-thymidine-labeled cells that were not immunoreactive for either glial cell marker and that showed neuronal characteristics was dramatically increased with adrenalectomy. These results suggest that adrenal hormones normally suppress the birth of both glia and neurons in the adult rat dentate gyrus.
The effect of acute exercise at three graded intensities on plasma growth hormone (GH) and prolactin (PRL) concentrations was examined in three groups of healthy male volunteers. According to their training status these subjects were divided into untrained, moderately trained and highly trained. A clear response of GH to exercise was registered already at an intensity of 50% of maximal oxygen uptake (VO2max) with a maximal response at 70% VO2max and no further effect at 90% VO2max. In contrast, no PRL response was observed at 50% VO2max, a small PRL rise was seen at 70% VO2max and the highest response occurred at 90% VO2max. Basal and exercise-stimulated plasma GH and PRL concentrations were similar in the three groups tested at similar relative workloads, suggesting that physical training induces adaptive changes whereby higher absolute workloads induce similar hormonal and metabolic changes. To examine a potential causative role of lactate in inducing the GH and PRL responses, sodium L-lactate was infused intravenously to normal sedentary volunteers at doses producing plasma lactate concentrations within the range of those seen between 70 and 90% VO2max. This resulted in a significant elevation of plasma GH and PRL concentrations, which, however, were smaller than those obtained at an exercise-induced matched plasma lactate concentration. We conclude that physical training causes adaptive changes in highly trained runners so that identical GH and PRL responses to exercise are recorded at higher absolute workloads. Lactate may be involved in the exercise-induced GH and PRL response; however, it does not appear to play an exclusive role.
Chronic stress produces structural changes and neuronal damage especially in the hippocampus. Because neurotrophic factors affect neuron survival, we questioned whether they might be relevant to the heightened vulnerability of hippocampal neurons following stress. To begin investigating this possibility, we examined the effects of immobilization stress (2 hr/d) on the expression of neurotrophic factors in rat brains using in situ hybridization. We found that single or repeated immobilization markedly reduced brain-derived neurotrophic factor (BDNF) mRNA levels in the dentate gyrus and hippocampus. In contrast, NT-3 mRNA levels were increased in the dentate gyrus and hippocampus in response to repeated but not acute stress. Stress did not affect the expression of neurotrophin-4, or tyrosine receptor kinases (trkB or C). Corticosterone negative feedback may have contributed in part to the stress-induced decreases in BDNF mRNA levels, but stress still decreased BDNF in the dentate gyrus in adrenalectomized rats suggesting that additional components of the stress response must also contribute to the observed changes in BDNF. However, corticosterone-mediated increases in NT-3 mRNA expression appeared to be primarily responsible for the effects of stress on NT-3. These findings demonstrate that BDNF and NT-3 are stress-responsive genes and raise the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus.
The neurotrophin gene family comprises four structurally related basic proteins, NGF, BDNF, NT-3 and NT-4/5. Despite high structural homology, these neurotrophins operate via different high-affinity membrane receptors, differ in target specificity, patterns of spatial and temporal distribution and responses to injury of the neuronal tissue. Based on the recent data, some aspects of BDNF and NT-3 neurotrophin activity and their possible role in normal and damaged nervous system are presented. Different effectiveness of exogenously applied neurotrophins in the injured brain as a consequence of responsiveness of particular neuronal populations to these factors, dose requirements, route of delivery, parenchymal penetration and target availability is discussed.
Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins (IL-Iα, IL-Iβ, ILIra and IL-2-IL-15), chemokines (IL-8/NAP-I, NAP-2, MIP-Iα and β, MCAF/MCP-I, MGSA and RANTES), tumor necrosis factors (TNF-α and TNF-β), interferons (INF-α, β and γ), colony stimulating factors (G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs), growth factors (EGF, FGF, PDGF, TGFα, TGFβ and ECGF), neuropoietins (LIF, CNTF, OM and IL-6), and neurotrophins (BDNF, NGF, NT-3-NT-6 and GDNF). The neurotrophins represent a family of survival and differentiation factors that exert profound effects in the central and peripheral nervous system (PNS). The neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF).
Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.
Brain-derived neurotrophic (BDNF), a member of the neurotrophin family, plays critical roles in the survival, growth, and maintenance of brain and peripheral neurons. We report the presence of BDNF protein in human platelets and its release upon agonist stimulation. The BDNF content of washed platelets varied widely, from 3.5 to 67 ng/4 × 108 platelets, averaging 25.2 ± 21.2 ng/4 × 108 platelets (mean ± SD). The BDNF concentration in platelet-poor plasma was low (1.7 ± 1.7 ng/ml, n = 11). Thrombin, collagen, the Ca++ ionophore A23187, and shear stress each induced a rapid release of BDNF from platelets. Up to only half of platelet BDNF was secreted upon agonist stimulation, suggesting that platelets may have a non-releasable pool of BDNF, or that the released BDNF binds to a recognition site on the platelet surface and is internalized, as occurs with serotonin. However, the cognate BDNF receptor. TrkB, was not detected in platelets. Nevertheless, the ability of BDNF to bind washed platelets was shown by FACS analysis confocal microscopy and by the binding and apparent internalization of [125I]-BDNF by platelets. A very high affinity site (Kd = 130 × 10-15 M, ∼80 sites/platelet) and a moderately high affinity site (Kd = 20 nM, ∼3750 sites/platelet) were identified. The BDNF content in two megakaryocytic cell lines, DAMI and Meg-01, was only 0.1% of the content measured in platelets. No BDNF mRNA was detected by Northern blotting in these cell lines or in platelets. The pituitary gland was also ruled out as a source for platelet BDNF, since the BDNF content of rat platelets did not decrease 2 weeks after hypophysectomy. Thus, platelet BDNF is not acquired from the megakaryocyte or pituitary gland, but is probably acquired from other sources via the blood circulation. Platelets appear to bind, store and release BDNF upon activation at the site of traumatic injury to facilitate the repair of peripheral nerves or other tissues that contain TrkB.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Brain derived neurotrophic factor (BDNF) promotes cholinergic neuron function and survival. In Alzheimer's disease, BDNF mRNA and protein are decreased in basal forebrain cholinergic neuron target tissues such as cortex and hippocampus. Using RT-PCR, we demonstrate that BDNF is synthesized in basal forebrain, supplying cholinergic neurons with a local as well as a target-derived source of this factor. BDNF mRNA levels are decreased 50% in nucleus basalis of Alzheimer disease patients compared to controls. Thus, not only do the basal forebrain cholinergic neurons have a reduced supply of target-derived BDNF, but also of local BDNF. We also show by Western blotting that human CNS tissue contains both proBDNF and mature BDNF protein. Moreover, we demonstrate a significant (2.25-fold) deficit in proBDNF protein in Alzheimer's disease parietal cortex compared to controls. Thus, reduced BDNF mRNA and protein levels in Alzheimer's disease suggests that BDNF administration may be an effective therapeutic strategy for this disorder.
Recent advances in understanding the role of neurotrophins on activity-dependent plasticity have provided insight into how behavior can affect specific aspects of neuronal biology. We present evidence that voluntary exercise can prime adult dorsal root ganglion neurons for increased axonal regeneration through a neurotrophin-dependent mechanism. Dorsal root ganglion neurons showed an increase in neurite outgrowth when cultured from animals that had undergone 3 or 7 days of exercise compared with sedentary animals. Neurite length over 18–22 h in culture correlated directly with the distance that animals ran. The exercise-conditioned animals also showed enhanced regrowth of axons after an in vivo nerve crush injury. Sensory ganglia from the 3- and 7-day-exercised animals contained higher brain-derived neurotrophic factor, neurotrophin 3, synapsin I, and GAP43 mRNA levels than those from sedentary animals. Consistent with the rise in brain-derived neurotrophic factor and neurotrophin 3 during exercise, the increased growth potential of the exercise-conditioned animals required activation of the neurotrophin signaling in vivo during the exercise period but did not require new mRNA synthesis in culture.
• neurotrophin
• gene expression
• plasticity
• neural activity
• experience
The ageing process and its associated diseases all involve perturbed energy metabolism, oxidative damage, and an impaired ability of the organism and its cells to cope with adversity. We propose that some specific signaling pathways in the brain may be important determinants of health during ageing. Among such specific signaling modalities are those activated in neurons by insulin-like growth factors (IGFs), brain-derived neurotrophic factor (BDNF) and serotonin. This triumvirate may be particularly important because of their cooperative influence on energy metabolism, food intake, stress responses and cardiovascular function. The health benefits to the periphery and central nervous system of dietary restriction and exercise may be mediated by this triumvirate of signals in the brain. At the molecular level, BDNF, serotonin and IGFs can all stimulate the production of proteins involved in cellular stress adaptation, growth and repair, neurogenesis, learning and memory and cell survival. The importance of this triumvirate is emphasized when it is seen that their general roles in energy metabolism, stress adaptation and disease resistance are conserved among diverse organisms consistent with important roles in the ageing process.
Resistance exercise has been shown to elicit a significant acute hormonal response. It appears that this acute response is more critical to tissue growth and remodelling than chronic changes in resting hormonal concentrations, as many studies have not shown a significant change during resistance training despite increases in muscle strength and hypertrophy. Anabolic hormones such as testosterone and the superfamily of growth hormones (GH) have been shown to be elevated during 15-30 minutes of post-resistance exercise providing an adequate stimulus is present. Protocols high in volume, moderate to high in intensity, using short rest intervals and stressing a large muscle mass, tend to produce the greatest acute hormonal elevations (e.g. testosterone, GH and the catabolic hormone cortisol) compared with low-volume, high-intensity protocols using long rest intervals. Other anabolic hormones such as insulin and insulin-like growth factor-1 (IGF-1) are critical to skeletal muscle growth. Insulin is regulated by blood glucose and amino acid levels. However, circulating IGF-1 elevations have been reported following resistance exercise presumably in response to GH-stimulated hepatic secretion. Recent evidence indicates that muscle isoforms of IGF-1 may play a substantial role in tissue remodelling via up-regulation by mechanical signalling (i.e. increased gene expression resulting from stretch and tension to the muscle cytoskeleton leading to greater protein synthesis rates). Acute elevations in catecholamines are critical to optimal force production and energy liberation during resistance exercise. More recent research has shown the importance of acute hormonal elevations and mechanical stimuli for subsequent up- and down-regulation of cytoplasmic steroid receptors needed to mediate the hormonal effects. Other factors such as nutrition, overtraining, detraining and circadian patterns of hormone secretion are critical to examining the hormonal responses and adaptations to resistance training.
Exercise is an important facet of behavior that enhances brain health and function. Increased expression of the plasticity molecule brain-derived neurotrophic factor (BDNF) as a response to exercise may be a central factor in exercise-derived benefits to brain function. In rodents, daily wheel-running exercise increases BDNF gene and protein levels in the hippocampus. However, in humans, exercise patterns are generally less rigorous, and rarely follow a daily consistency. The benefit to the brain of intermittent exercise is unknown, and the duration that exercise benefits endure after exercise has ended is unexplored. In this study, BDNF protein expression was used as an index of the hippocampal response to exercise. Both daily exercise and alternating days of exercise increased BDNF protein, and levels progressively increased with longer running duration, even after 3 months of daily exercise. Exercise on alternating days was as effective as daily exercise, even though exercise took place only on half as many days as in the daily regimen. In addition, BDNF protein remained elevated for several days after exercise ceased. Further, after prior exercise experience, a brief second exercise re-exposure insufficient to cause a BDNF change in naïve animals, rapidly reinduced BDNF protein to levels normally requiring several weeks of exercise for induction. The protein reinduction occurred with an intervening "rest" period as long as 2 weeks. The rapid reinduction of BDNF by an exercise stimulation protocol that is normally subthreshold in naïve animals suggests that exercise primes a molecular memory for BDNF induction. These findings are clinically important because they provide guidelines for optimizing the design of exercise and rehabilitation programs, in order to promote hippocampal function.
Exercise represents a physical stress that challenges homeostasis. In response to this stressor, the autonomic nervous system and hypothalamus-pituitary-adrenal axis are known to react and participate in the maintenance of homeostasis and the development of physical fitness. This includes elevation of cortisol and catecholamines in plasma. However, physical conditioning is associated with a reduction in pituitary-adrenal activation in response to exercise. On the other hand, highly trained athletes exhibit chronic mild hypercortisolism at baseline that may be an adaptive change to chronic exercise. In addition the proinflammatory cytokine, IL-6 is also activated, probably via catecholamines. On the other hand, the stress of chronic exercise induces certain changes to the thyroid axis. Peripheral thyroid hormone metabolism suppression is observed, and the result is a hormonal status similar to that of euthyroid sick syndrome (ESS), with suppression of T3 and elevation of rT3 plasma levels. One mechanism proposed involves exercise-activated pathways participating in the pathogenesis of ESS. This is realized through norepinephrine's activation of NF-kappaB. Neuroendocrine response to exercise stress involves activation of NF-kappaB resulting in inactivation of T3-dependent 5'-deiodinase gene expression and enzyme activity. Thus, ESS is generated in the periphery. On the other hand, activation and nuclear translocation of NF-kappaB leads to increased transcription of proinflammatory genes responsible for the expression of proinflammatory cytokines such as TNF-alpha and IL-6. These cytokines could activate cortisol, which in turn inhibits NF-kappaB activation through IkappaB and finally shuts down this cycle.
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Hypothalamic-pituitary-adrenal (HPAA) and -gonadal (HPGA) axis modification and cognitive impairments have been reported in elderly subjects and related to physical training status. The aim of this study was to investigate if HPAA and HPGA regulation are altered in elderly distance runners (RUNI; n = 8; age: 68.9 ± 4.2 yrs; training: 65±20km/wk over the last 20yrs; means ± SD) or are affected in elderly sedentary indiividuals (SED; n = 11; age: 69.1 ± 2.6yrs) by an aerobic training over 20 weeks (3 times/week, 30-60 min walking), respectively. The protocol included assessment of the hormone profile iin basal non-suppressed state as well as evaluation of hormonal [responses to dexamethasone (DEX, 1.5 mg) induced adrenal suppression, to post-DEX combined corticotrophin releasing hormone (CRH; 0.7μg/kg) and luteinizing hormone releasing hormone (LHRH, 0.7μg/kg) stimulation and to exercise challenge (30 min cycle ergometry at 65 % V02max). Mental functions influenced by HPAA and HPGA activity were also assessed in RUN aind SED before (SED-PRE) and after (SED-POST) the training program. Basal and post-DEX plasma concentrations of adrenocorticotropic hormone (ACTH), Cortisol (CSL), luteinizing hormome (LH), follicle stimulating hormone (FSH) and testosterone (T) did not differ between RUN and SED-PRE. Basal plasma free T concentration was significantly lower in RUN (RUN: 10.23 ± 2.41 pg · ml⁻¹ vs. SED-PRE: 16.6 ± 5.59 pg · ml⁻¹). During releasing hormone challenge test after DEX administration (DEX/RH), no differences. were found between RUN and SED-PRE in plasma ACTH, LH, FSH and T response. During this stimulation test, plasima CSL was significantly higher in RUN than in SED-PRE after 90min (RUN: 5.86 ± 3.65 μg · dl⁻¹ vs. SED-PRE: 2.74 ± 2.09 μg · dl⁻¹). Differences in plasma CSL concentrations between groups w/ere not induced by 30-min exercise challenge. Basal hormone profile was not altered by training in SED. During DEX/RH only plasma
ACTH concentration was significantly higher in SED-POST compared to SED-PRE. Long and short-term memory function did not differ between RUN, SED-PRE and SED-POST. Our data suggest that following post-DEX CRH/LHRH challenge elderly endurance athletes reveal-in the absence of altered peak values-a pattern of prolonged secretion of glucocorticoids. However, the high interindividual variability of plasma ACTH and CSL concentrations shows that reduced corticotropic sensitivity to negative feedback is not always induced by chronic exercise stress. Lower plasma free T concentrations in RUN compared to SED are not caused by modified LH synthesis-secretion capacity.
Key words
Aging - dexamethasone - releasing hormones - reproductive system - training
The importance of hormones in regulating physiological functions and processes has intrigued scientists since they were first characterized by Baylis and Starling in 1904 (1). Research advances in endocrinology have led to an improved understanding of the intricate and diverse functions of the endocrine system. In addition, advances in technology and analytical procedures have facilitated the convenience and accuracy of hormone measurements. These advancements have facilitated the proliferation of endocrine research in exercise and sport science over the past 30 years (Fig. 1). This relative explosion in research related to exercise endocrinology has contributed greatly to the understanding of the physiological consequences of exercise and physical training. Nevertheless, the emerging research is often inconsistent, contradictory, and difficult to interpret. In some cases, research discrepancies may be explained by methodological or analytical inconsistencies.
An interactive blood-brain barrier (BBB) helps regulate the passage of peptides from the periphery to the CNS and from the CNS to the periphery. Many peptides cross the BBB by simple diffusion, mainly explained by their lipophilicity and other physicochemical properties. Other peptides cross by saturable transport systems. The systems that transport peptides into or out of the CNS can be highly specific, transporting MIF-1 but not Tyr-MIF-1, PACAP38 but not PACAP27, IL-1 but not IL-2, and leptin but not the smaller ingestive peptides NPY, orexin A, orexin B, CART (55-102[Met(O)(67)]), MCH, or AgRP(83-132). Although the peptides EGF and TGF-alpha bind to the same receptor, only EGF enters by a rapid saturable transport system, suggesting that receptors and transporters can represent different proteins. Even the polypeptide NGF enters faster than its much smaller subunit beta-NGF. The saturable transport of some compounds can be upregulated, like TNF-alpha in EAE (an animal model of multiple sclerosis) and after spinal cord injury, emphasizing the regulatory role of the BBB. As has been shown for CRH, saturable transport from brain to blood can exert effects in the periphery. Thus, the BBB plays a dynamic role in the communication of peptides between the periphery and the CNS.
Altered neural-endocrine relations have been proposed as factors in mammalian aging. In the same rats from three age groups we quantified astrocyte reactivity in hippocampus, performed radioimmunoassays for plasma adrenocorticoids, and measured adrenal weight. These variables were correlated in individual animals and generally increased with age. The findings are consistent with recent hypotheses that endocrine levels are related to brain aging, either as cause or effect.
To explore the effects of repeated episodes of hypercortisolemia on hypothalamic-pituitary-adrenal axis regulation, we studied plasma ACTH and cortisol (CORT) responses to 100 micrograms human CRH (hCRH) in 10 dexamethasone (1.5 mg)-pretreated elderly endurance athletes who had abstained from physical activity for at least 48 h before testing and 13 sedentary age-matched controls. Basal CORT and ACTH levels were indistinguishable between runners and sedentary controls, whereas CORT responses to hCRH were significantly increased in endurance athletes, and ACTH responses tended to be higher in this group. Comparing the dexamethasone/hCRH test results of the runners with those of an age-matched sample of previously studied depressed patients (n = 9), similar hormone responses to CRH challenge were noted. The mechanisms underlying these alterations may either be a stepwise decrease in corticotropic sensitivity to the negative feedback signal leading to a switch to positive glucocorticoid feedback, an enhanced cosecretion of ACTH secretagogues such as vasopressin, or a combination of both. In conclusion, hypothalamic-pituitary-adrenal axis physiology seems to be determined by previous stressful events associated with hypercortisolemia, regardless of its etiology.
Twelve non-specifically trained volunteers (aged 26.5 years, SD 3.6) performed exhausting incremental graded exercise (ST) and 1-min anaerobic cycle ergometer exercise (AnT) at 2-h intervals for the purpose of investigating beta-endorphin (beta-E) behaviour dependent on exercise intensity and anaerobic metabolism. In order to determine [beta-E], adrenocorticotropic hormone [ACTH], cortisol [C], adrenaline [A] and noradrenaline [NA] concentrations, venous blood samples were collected prior and subsequent to exercise until the 20th min of the recovery period, as well as in ST before and after exceeding the individual anaerobic threshold (THan,i). Before, during and after ST, lactate concentration, heart rate and perceived degree of exertion were also determined; after AnT maximum lactate concentration was measured. Both types of exercise led to significant increases in [beta-E], [ACTH], [A] and [NA], with levels of [beta-E] and [ACTH] approximately twice as high after ST as after AnT. The [C] increased significantly only after ST. During ST significant changes in [beta-E] and [ACTH] were measured only after exceeding THan,i. At all measuring times before and after ST and AnT both hormones correlated positively. In AnT the increases of [beta-E] and [A] demonstrated a correlation (r = 0.65; P less than 0.05). Both in AnT and ST there was a relationship between the maximum concentrations of beta-E and lactate (r = 0.63 and 0.71; each P less than 0.05). We therefore conclude that physical exercise with increasing or mostly anaerobic components leads to an increase in [beta-E], the extent correlating with the degree of lactate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Serum PRL, GH and cortisol values were evaluated in 7 athletes and 7 sedentary adult subjects after a submaximal and an exhaustive exercise-tests. A significant increase of serum PRL was recorded after the exhaustive exercise in athletes only. Serum GH concentration increase was significant after both exercises and quantitatively surposable in both groups. Serum cortisol concentration underwent an increase after the exhaustive but not after the submaximal exercises in both groups.
Glucocorticoids (GCs), the adrenal steroids secreted during stress, can damage the hippocampus, a principal neural target site for GCs. The extent of cumulative exposure to GCs influences the rate of neuron loss in the aging hippocampus, such that stress can accelerate senescent hippocampal degeneration. Moreover, under circumstances where GC exposure is insufficient to damage neurons, the hormones impair the capacity of neurons to survive neurological insults such as hypoxia-ischemia, seizure, or hypoglycemia. Considerable progress has been made in understanding how GCs endanger hippocampal neurons. The effect is a direct one, in that the endangerment is mediated by GC receptors and occurs in cultured hippocampal neurons. The endangerment is energetic in nature--the insults worsened by GCs represent energetic crises, and the GC endangerment is prevented by supplementation of neurons with energy substrates. As the likely mechanism by which GCs induce an energetic vulnerability, the steroids inhibit glucose transport in hippocampal neurons and glia. As a result of this effect of GCs upon energetics is that neurons are less capable of the costly task of containing the damaging fluxes of glutamate and calcium triggered by the neurological insults. Thus, following such insults, GCs disrupt glutamate removal and elevate synaptic glutamate concentrations, enhance the magnitude and duration of the subsequent mobilization of free cytosolic calcium, and exacerbate the magnitude of calcium-dependent degenerative events. Thus, stress has the capacity to damage the hippocampus and exacerbate the toxicity of some common neurological disorders; nevertheless, some behavioral interventions are known to cause sustained diminution of GC concentrations, and thus have the potential to protect the hippocampus from these deleterious effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment with excitotoxin kainic acid is known to increase the level of messenger RNAs for nerve growth factor and brain-derived neurotrophic factor in the brain. In this study we have used quantitative in situ hybridization to analyse the effect of glucocorticoids on kainic acid-induced increase of nerve growth factor and brain-derived neurotrophic factor messenger RNA in the rat brain. In adrenalectomized animals, the kainic acid-mediated increase of brain-derived neurotrophic factor messenger RNA in the hippocampus and the cerebral cortex was reduced by 50% compared to sham-operated animals. The increase of nerve growth factor messenger RNA elicited by kainic acid in the dentate gyrus was almost completely abolished in adrenalectomized animals. No significant change was seen in c-fos messenger RNA in the hippocampus of adrenalectomized rat after kainic acid injection compared to sham-operated kainic acid-treated rats, while a three-fold reduction was seen in the cerebral cortex. Dexamethasone injection prior to kainic acid administration potentiated the kainic acid-induced increase of nerve growth factor messenger RNA in the dentate gyrus and the piriform cortex. In contrast, dexamethasone pretreatment did not potentiate the kainic acid-mediated increase of brain-derived neurotrophic factor messenger RNA. We also examined the effect of adrenalectomy and kainic acid injection on tropomyosin receptor kinase B and C messenger RNA, encoding essential components of high-affinity receptor for brain-derived neurotrophic factor/neurotrophin-4 and neurotrophin-3, respectively. Following adrenalectomy no change of tropomyosin receptor kinase B or C messenger RNA was detected in any of the brain regions studied compared to sham-operated animals. The injection of kainic acid caused four-fold and two-fold increases of tropomyosin receptor kinase B messenger RNA in the dentate gyrus and cerebral cortex, respectively, but no change in tropomyosin receptor kinase C messenger RNA in any of these regions. In adrenalectomized animals receiving kainic acid, the level of tropomyosin receptor kinase B messenger RNA was decreased both in the dentate gyrus and cerebral cortex as compared to sham animals treated with kainic acid. Taken together, the data suggest that excitotoxins and glucocorticoids both influence expression of brain-derived neurotrophic factor and nerve growth factor messenger RNA in the brain, but by two different mechanisms, where the effect of excitotoxin-evoked seizures is modulated by glucocorticoids.
As described in the preceding paper, adrenalectomy triggers hippocampal granule cell degeneration that begins within days after adrenalectomy, continues for months, and is the only apparent cell death anywhere within the brain. At the light microscopic level, granule cell degeneration is characterized by coalescing of nuclear chromatin into numerous spherical bodies. Since the morphology at the light microscopic level resembled the nuclear morphology characteristic of "apoptosis" rather than "necrosis," we undertook this ultrastructural study to determine if adrenalectomy induces the morphological features characteristic of apoptosis. Electron microscopy revealed coalescing of nuclear chromatin, compaction of cytoplasm, and the budding-off of cytoplasmic bodies that were engulfed by glia. Mitochondria, the Golgi apparatus, and rough endoplasmic reticulum appeared relatively normal early in the process of granule cell degeneration when nuclear changes were prominent. Presynaptic terminals innervating degenerating granule cells appeared normal. Electron-dense degeneration of granule cell axon terminals in association with normal postsynaptic elements of CA3 pyramidal cells highlighted the extraordinary selectivity of adrenalectomy-induced granule cell death. Ten weeks after adrenalectomy, astrocytes were filled with abnormally abundant glial fibrils and neuronal debris. This "apoptotic" morphology produced by adrenalectomy was clearly distinct from the "necrotic" granule cell morphology produced by intrahippocampal injection of the neurotoxin volkensin. These results indicate that, in a manner possibly analogous to castration-induced prostate cell death, loss of adrenal hormone triggers a process in dentate granule cells that causes the morphological changes characteristic of "apoptosis." Thus, adrenal steroids may be obligatory growth factors for dentate granule cells and their loss may initiate a selective process in the mature brain that is unique or that may normally occur only in the developing brain.
Glucocorticoid hormones are important regulators of brain development and ageing, and can impair the capacity of hippocampal neurones to survive various neurological insults. Here we show that dexamethasone, a synthetic glucocorticoid, prevents activity-dependent increases of brain-derived neurotrophic factor (BDNF) mRNA in cultures of rat hippocampal neurones. In situ hybridization was used to evaluate the levels of BDNF mRNA. Up-regulation of BDNF mRNA triggered by depolarization with high potassium, or exposure to the glutamate receptor agonist kainic acid, resulted both from higher levels of expression in neurones and from new recruitment of cells. These data suggest that the known ability of glucocorticoids to exacerbate neuronal injury following ischaemia and other metabolic insults could be due to antagonism of regulatory mechanisms governing neurotrophin levels in the brain.
Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) support the viability and function of many types of neurons, and are likely mediators of activity-dependent changes in the CNS. We examined BDNF and NGF mRNA levels in several brain areas of adult male rats following 0, 2, 4, or 7 nights with ad libitum access to running wheels. BDNF mRNA was significantly increased in several brain areas, most notably in the hippocampus and caudal 1/3 of cerebral cortex following 2, 4, and 7 nights with exercise. Significant elevations in BDNF mRNA were localized in Ammon's horn areas 1 (CA1) and 4 (CA4) of the hippocampus, and layers II-III of the caudal neocortex and retrosplenial cortex. NGF mRNA was also significantly elevated in the hippocampus and caudal 1/3 of the cortex, affecting primarily the dentate gyrus granular layer (DG) and CA4 of the hippocampus and layers II-III in caudal neocortex.
A comparison was made of the permeabilities of different neurotrophic factors at the blood-brain barrier (BBB) and blood-nerve barrier (BNB) in normal adult rats by quantifying the permeability coefficient-surface area (PS) product after correction for the residual plasma volume (Vp) occupied by the protein in the capillary bed of the nerve endoneurium or different brain regions. The i.v. bolus injection technique was used in the cannulated brachial vein and artery using the same protein radioiodinated with a second isotope of iodine (125I vs. 131I) to separately determine the PS and Vp values. The plasma washout showed a decreasing plasma half-life in the order of brain-derived neurotrophic factor (BDNF) < neurotrophin-3 (NT-3) < ciliary neurotrophic factor (CNTF) < nerve growth factor (NGF). The PS at the BNB for NGF was 1.40 +/- 0.15 x 10(-6) ml/g/s (mean +/- SEM). The other neurotrophic proteins were all significantly higher than NGF (CNTF: 9.5 x ; NT-3: 20.8 x ; BDNF: 18.9 x ). The Vp for NGF at the BNB was 1.92 +/- 0.12 microliters/g and was not significantly different from the other proteins except for NGF vs. BDNF (P < 0.05). The PS for NGF at the BBB ranged from 1.5 to 2.7 x 10(-6) ml/g/s for six different brain regions. The PS for CNTF ranged from 6.0 to 8.0-fold higher than NGF; NT-3: 10.6 to 15.2-fold higher; and BDNF: 11.3 to 16.4-fold higher. The Vp values were not significantly different except for CNTF in the hippocampus and cortex (P < 0.05). SDS-PAGE analyses of all the radioiodinated neurotrophic proteins after 60 min of uptake revealed intact protein in the endoneurium and in the six different brain regions with exposure times of 2-42 days. The quantification of the permeability of these neurotrophic proteins provides baseline values for comparison of different protein modifications that enhance the PS while still preserving the neurotrophic activity (e.g., protein glycation; Poduslo and Curran, Mol. Brain Res., 23 (1994) 157). Enhanced permeability following modification might allow the use of systematic delivery of these proteins for practical therapeutic treatment of various neurodegenerative disorders.
Previous results from our laboratory indicate that two nights of voluntary wheel running upregulates brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. In order to investigate the time-course of the BDNF response and to examine how physical activity preferentially activates particular transcriptional pathways, the effects of 6 and 12 h of voluntary wheel running on BDNF and exons I-IV mRNA expression were investigated in rats. Hippocampal full-length BDNF mRNA expression was rapidly influenced by physical activity, showing significant increases in expression levels as soon as 6 h of voluntary wheel running. Moreover, there was a strong positive correlation between distance run and BDNF mRNA expression. Exon I mRNA expression was significantly upregulated after 6 h of running and was maintained or enhanced by 12 h of voluntary running. Exon II had a slower time-course and was significantly upregulated after 12 h, selectively in the CA1 hippocampal region. Exon III and Exon IV showed no significant increase in expression level after 6 or 12 h of running in the paradigm studied. It is significant that the rapid neurotrophin response is demonstrated for a physiologically relevant stimulus, as opposed to the extreme conditions of seizure paradigms. Furthermore, exercise-induced upregulation of BDNF may help increase the brain's resistance to damage and neurodegeneration that occurs with aging.
Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent for degenerative disorders of the central nervous system. In this report, we investigated the ability of BDNF to cross the blood-brain barrier (BBB). BDNF was stable in blood up to 60 min after i.v. injection, with evidence for aggregation, and had an early, rapid influx into brain. By 10 min, most of the BDNF sequestered by the cerebral cortex was associated with the parenchyma rather than with the endothelial cells, demonstrating complete passage across the BBB. A small dose of unlabeled BDNF enhanced the entry of 125I-BDNF from blood to brain after an i.v. bolus injection, whereas larger doses had no effect. In contrast, a large dose of unlabeled BDNF inhibited the influx of 125I-BDNF during in situ brain perfusion. After intracerebroventricular injection, the efflux of BDNF from brain to blood occurred at a rate similar to that for reabsorption of cerebrospinal fluid, and no evidence for self-inhibition was found. Therefore, we conclude that intact BDNF in the peripheral circulation crosses the BBB by a high-capacity, saturable transport system.
Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.
Hypothalamic-pituitary-adrenal (HPAA) and -gonadal (HPGA) axis modification and cognitive impairments have been reported in elderly subjects and related to physical training status. The aim of this study was to investigate if HPAA and HPGA regulation are altered in elderly distance runners (RUN; n = 8; age: 68.9+/-4.2 yrs; training: 65+/-20 km/wk over the last 20 yrs; means +/- SD) or are affected in elderly sedentary individuals (SED; n = 11; age: 69.1+/-2.6 yrs) by an aerobic training over 20 weeks (3 times/week, 30-60 min walking), respectively. The protocol included assessment of the hormone profile in basal non-suppressed state as well as evaluation of hormonal responses to dexamethasone (DEX, 1.5 mg) induced adrenal suppression, to post-DEX combined corticotrophin releasing hormone (CRH; 0.7 microg/kg) and luteinizing hormone releasing hormone (LHRH, 0.7 microg/kg) stimulation and to exercise challenge (30 min cycle ergometry at 65% VO2max). Mental functions influenced by HPAA and HPGA activity were also assessed in RUN and SED before (SED-PRE) and after (SED-POST) the training program. Basal and post-DEX plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol (CSL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T) did not differ between RUN and SED-PRE. Basal plasma free T concentration was significantly lower in RUN (RUN: 10.23+/-2.41 pg x ml(-1) vs. SED-PRE: 16.6+/-5.59 pg x ml(-1)). During releasing hormone challenge test after DEX administration (DEX/RH), no differences were found between RUN and SED-PRE in plasma ACTH, LH, FSH and T response. During this stimulation test, plasma CSL was significantly higher in RUN than in SED-PRE after 90 min (RUN: 5.86+/-3.65 microg x dl(-1) vs. SED-PRE: 2.74+/-2.09 microg x dl(-1)). Differences in plasma CSL concentrations between groups were not induced by 30-min exercise challenge. Basal hormone profile was not altered by training in SED. During DEX/RH only plasma ACTH concentration was significantly higher in SED-POST compared to SED-PRE. Long and short-term memory function did not differ between RUN, SED-PRE and SED-POST. Our data suggest that following post-DEX CRH/LHRH challenge elderly endurance athletes reveal-in the absence of altered peak values-a pattern of prolonged secretion of glucocorticoids. However, the high interindividual variability of plasma ACTH and CSL concentrations shows that reduced corticotropic sensitivity to negative feedback is not always induced by chronic exercise stress. Lower plasma free T concentrations in RUN compared to SED are not caused by modified LH synthesis-secretion capacity.
Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release. Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression. Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.
Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family and has been shown to be a potent and effective trophic factor for motor neurons and other neurons of the peripheral and central nervous. Little is known, however, about the relationship between the efficacy and pharmacokinetics of s.c. administered BDNF. In this study, the efficacy of BDNF on motor neuron protection in sciatic or facial nerve axotomy models was examined and compared with the concommitant concentrations of BDNF in plasma. Delayed treatment (started at 1 week after surgery) of BDNF was also shown to retard choline acetyltransferase reduction in sciatic nerve axotomy models.
Serotonin (5-HT), one of the evolutionary oldest central neurotransmitters, regulates the most extensive modulatory behavioral system in the brain of vertebrates. 5-HT projections are influenced by extrinsic and intrinsic impulses from different cortical brain areas, which reach Raphe nuclei over feedback loops, containing external and internal body information about planning, evaluation, motivation or excitation. Serotonergic neurotransmission adjusts neuromodulation with consecutive adequate stimulation of the neuronal network. This depends on appropriate equilibration of presynaptic 5-HT storage and release but also on 5-HT reuptake from synaptic cleft by 5-HT transporters. The associated pre and postsynaptic 5-HT receptor cooperation, postsynaptic second messenger response and phosphoinositide signaling mediated by postsynaptic 5-HT(2) receptor subpopulation alter signal transduction in which myristolated alanine rich C kinase substrate is prominently involved in regulation of further central 5-HT areas in the brain and corresponding functional neuronal changes. Even though the central function of 5-HT neurotransmission is dominating in the multifold behavioral regulation, peripheral concentration of tryptophan (TRP) adjusted by hepatic and non-hepatic TRP pyrrolase, TRP liberation from albumin especially by adrenergic stimulation of free fatty acids, TRP passage across the blood-brain barrier and TRP hydroxylase activity are also important for appropriate 5-HT neurotransmission as they affect central 5-HT synthesis. The high adaptability of 5-HT neurotransmission is able to compensate neuromodular dysfunctions in the brain by mechanisms which mediate 5-HT biosynthesis, release, reuptake, pre and postsynaptic receptor stimulation with the respective second messenger response and signal transduction to various areas of the brain which are involved in regulation of behavior, mood, memory, learning and attenuation of obsession, depending on the different vigilance states of the subject. Adequate 5-HT system function supports regulation of intercommunicative neuronal transmission in the brain, which optimizes behavioral neuromodulation during and after transient disturbances of neuromodular behavior caused by stress-induced exertions, but also in permanent disorder such as major depression. Serotonergic neurotransmission improves the clinical course due to compensatory 5-HT impulse correction. This hypothetical interpretation of the serotonergic central neuromodular regulation and interaction with the neuronal network is supported by findings both in functional disturbances and persistent impairments in mental disorders. A comparison of the symptomatology in permanent and transient disturbance of brain neuromodulation enhances our basic knowledge on the regulative factors e. g. in endogenous depression and depressive behavioral changes after exhaustive exercise. This consideration exhibits that the interaction between altered central neuromodulation and peripheral metabolic and hormonal dysfunctions is able to differentiate the etiology of the symptoms. It is suggested that the central neuromodular disturbance of stress-induced causes might initiate the manifestation of the impairment. The theoretical background of this hypothesis is discussed in the present review.
COTMAN, C.W., and C. ENGESSER-CESAR. Exercise enhances and protects brain function. Exerc. Sport Sci. Rev., Vol. 30, No. 2, pp. 75–79, 2002. Physical activity, in the form of voluntary wheel running, induces gene expression changes in the brain. Animals that exercise show an increase in brain-derived neurotrophic factor, a molecule that increases neuronal survival, enhances learning, and protects against cognitive decline. Microarray analysis of gene expression provides further support that exercise enhances and supports brain function.
Responses of plasma prolactin (PRL) concentration to alterations in carbon dioxide pressure ( pCO(2)) induced by 4 min of rebreathing out of a bag with 6 l gas initially containing a concentration of 93% O(2) and 7% CO(2) (hypercapnia hyperoxia; HH) and 4 min of voluntary hyperventilation (VH) at a respiratory rate of 28 - 32 per minute were investigated in ten males. During rebreathing in HH, an augmentation of pCO(2) from 40.2 +/- 2.1 to 63.7 +/- 5.4 mmHg and a decrease of pH from 7.4 +/- 0.02 to 7.32 +/- 0.04 were found in capillary blood (p < 0.01). Neither breathing frequency (BF) nor plasma PRL changed during this period. After two minutes of post-rebreathing, pCO(2) and pH returned to basal values. BF increased from 2 min of rebreathing (12.4 +/- 1.9 breath/min) until 11 min of recovery period (18.1 +/- 4.9 breath/min) (p < 0.01), while plasma PRL increased from end of rebreathing (11.59 +/- 1.49 ng/dl) to 11 min of recovery period (13.63 +/- 1.97 ng/dl) (p < 0.01). In VH, hyperventilation decreased pCO (2) from 39.91 +/- 2.62 to 21.73 +/- 2.59 mmHg (p < 0.01) and increased pH from 7.39 +/- 0.04 to 7.58 +/- 0.04 (p < 0.01) in capillary blood. After four minutes of recovery from hyperventilation, pH and pCO(2) were back to their basal values. No changes in plasma PRL were found throughout VH. This present pilot study's new finding is that plasma PRL increases after hypercapnia acidosis. This indicates that acidosis-induced central chemoreflex function increases phrenic nerve activity based on serotonergic modulation, leading to an augmentation of BF. As serotonin is also the main PRL-releasing factor, this might have had the collateral effect of causing PRL release and delayed appearance in the peripheral circulation.
Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.
Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.
Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging.
Glucocorticoids regulate plasticity and survival of hippocampal neurons. Aberrant exposure to this steroid hormone can result in neurodegeneration, perhaps secondary to disruption of calcium homeostasis. Calbindin, a calcium-binding protein that buffers excess calcium, may protect against neurodegeneration resulting from overabundance of intracellular calcium. In this study, we examined whether chronic treatment (1 year) with cortisol enhances hippocampal calbindin expression in primates. Calbindin is a marker for inhibitory neurons and the dentate gyrus is known to adopt an inhibitory phenotype in response to extreme conditions such as seizures. Thus, we hypothesized that chronic cortisol exposure may also promote a GABAergic phenotype. Therefore, we examined the expression of the GABA-synthesizing enzyme glutamic acid decarboxylase. The expression of brain-derived neurotrophic factor, which is responsive to glucocorticoids, was also examined. Our results demonstrate significant increases in calbindin, glutamic acid decarboxylase and brain-derived neurotrophic factor in several regions of the primate hippocampus, including the dentate gyrus and CA3, in response to chronic cortisol exposure. These results suggest that chronic cortisol exposure may shift the balance towards a GABAergic phenotype, perhaps as part of a compensatory feedback mechanism to dampen the initial excitatory effects of glucocorticoids in the hippocampus.
We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.
Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the adult. BDNF is known to be stored in human platelets and to circulate in plasma, but the regulation and function of BDNF in peripheral blood is still poorly understood. In this prospective study, we have examined 140 healthy, non-allergic adults (20-60 years old) to elucidate the impact of age and physical parameters on BDNF levels in human platelets and plasma. There was a wide concentration range of BDNF in serum (median: 22.6 ng/ml), platelets (median: 92.7 pg/10(6) platelets) and plasma (median: 92.5 pg/ml). BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not. When matched for weight, there were no significant gender differences regarding BDNF plasma levels. However, women displayed significantly lower platelet BDNF levels than men. In addition, platelet BDNF levels changed during the menstrual cycle. In conclusion, we demonstrate that parameters such as age or gender have a specific impact on stored and circulating BDNF levels in peripheral blood.
The purpose of the present investigation was to examine androgen receptor (AR) content in the vastus lateralis following two resistance exercise protocols of different volume. Nine resistance-trained men (age=24.3+/-4.4 years) performed the squat exercise for 1 (SS) and 6 sets (MS) of 10 repetitions in a random, counter-balanced order. Muscle biopsies were performed at baseline, and 1h following each protocol. Blood was collected prior to, immediately following (IP), and every 15 min after each protocol for 1h. No acute elevations in serum total testosterone were observed following SS, whereas significant 16-23% elevations were observed at IP, 15, and 30 min post-exercise following MS. No acute elevations in plasma cortisol were observed following SS, whereas significant 31-49% elevations were observed for MS at IP, 15, and 30 min post-exercise. Androgen receptor content did not change 1h following SS but significantly decreased by 46% following MS. These results demonstrated that a higher volume of resistance exercise resulted in down-regulation of AR content 1h post-exercise. This may have been due to greater protein catabolism associated with the higher level of stress following higher-volume resistance exercise.
Neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to play an important role in neuronal repair and plasticity. Recent experimental evidence suggests neuroprotective effects of these proteins in multiple sclerosis (MS). We investigated the response of serum NGF and BDNF concentrations to standardized acute exercise in MS patients and controls. Basal NGF levels were significantly elevated in MS. Thirty minutes of moderate exercise significantly induced BDNF production in MS patients and controls, but no differential effects were seen. We conclude that moderate exercise can be used to induce neutrophin production in humans. This may mediate beneficial effects of physical exercise in MS reported recently.