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Oral supplementation with melon superoxide dismutase extract promotes antioxidant defences in the brain and prevents stress-induced impairment of spatial memory
Abstract
The purpose of this study was to investigate the effect of antioxidant ingestion on stress-induced impairment of cognitive memory. Male C57BL/6 mice were divided into four groups as follows: (1) control mice (C mice) fed in a normal cage without immobilization; (2) restraint-stressed (RS mice) fed in a small cage; (3) vitamin E mice (VE mice), mice were fed in a small cage with a diet supplemented with vitamin E; (4) GliSODin mice (GS mice) fed in a small cage with a diet supplemented with GliSODin. RS, VE and GS mice were exposed to 12 h of immobilization daily. Five weeks later, spatial learning was measured using the Morris Water Maze (MWM) test. After water maze testing, we performed immunohistochemical analysis using 4-hydroxy-2-noneral (4-HNE) and an anti-Ki67 antibody. 4-HNE is a marker of lipid peroxidation. RS mice showed impaired spatial learning performance and an increased number of 4-HNE-positive cells in the granule cell layer (GCL) of the hippocampal dentate gyrus when compared to C mice. Moreover, RS mice showed a decreased number of Ki67-positive cells in the subgranular zone (SGZ). GS mice showed better spatial learning memory than RS mice. The number of 4-HNE-positive cells in the GCL of GS mice was significantly less than that of RS mice. The number of Ki67-positive cells in the SGZ of GS mice was significantly greater than that of RS mice. These finding suggests that GliSODin prevents stress-induced impairment of cognitive function and maintains neurogenesis in the hippocampus through antioxidant activity.
... The effects of coated-SOD ingestion on cognition are also documented. For example, stress-induced impairment of cognitive memory was alleviated by SOD-Gliadin treatment in a C57BL/6 model [36]. In these experiments, stress was induced by physical restraint daily for 12 h over the course of 5 weeks. ...
... Such events might depend on the transactivation of transcription factors through the antioxidant response element (ARE) / nuclear factor E2-related factor (Nrf2) axis [40]. Others have hypothesized a role for nitric oxide (NO) [36]. In this case, NO might be generated at the intestines and later released in the blood as a response to non-self SOD-Gliadin. ...
... A C C E P T E D ACCEPTED MANUSCRIPT Animal model of stress-induced impairment of spatial memory [36] Note: None of the above mentioned studies report adverse side effects of oral supplementation with SOD. =increased =decreased. ...
Dietary antioxidant supplementation has been popular in Western countries. Various supplements have been developed in recent years, and research has been gathered from both animal and clinical research trials. In this review, the therapeutic value of oral administration of a combination of melon superoxide dismutase (SOD) and a vegetable polymer (gliadin) is evaluated. Critical examination of the effects of SOD-gliadin supplementation is carried out, with an emphasis on its impact on oxidative stress levels and on endogenous antioxidant pathways. Overall analysis of peer-reviewed published data suggests that intake of SOD-gliadin might have advantageous health effects. These conclusions are dependent on the condition or pathology under consideration. In general, the authors, who analyzed SOD-gliadin supplementation, support the use of SOD-gliadin supplementation as a complementary treatment rather than a therapeutic treatment. To further clarify the importance of dietary SOD-gliadin administration, additional large-scale clinical trials are recommended.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
... Administration of strawberry extract offered protection against spatial memory deficits induced by whole-body irradiation [10]. In addition, GliSODin, a superoxide dismutase (SOD) extracted from melons and combined with gliadin, prevents stress-induced impairment of cognitive function and maintains neurogenesis in the hippocampus [11]. ...
... The mice were randomly divided into four groups consisting of 10 mice each: Control mice (C mice), Restraint-stressed mice (RS mice), Restraint-stressed mice supplemented with Noni (Noni mice), and Restraint-stressed mice supplemented with Vitamin E mice (VE mice). Each mouse with restraint stress was placed in a 3 × 3 × 7.5 cm stainless-steel cage, which completely restricted their movement, but allowed them to drink water ad libitum [4,11]. Immobilization stress was given 8 h per day (0900-1700 h) for 6 days each week. ...
... In addition, the Noni mice showed a significantly shorter latency than the RS mice on Day 16. No difference between the VE and C mice was observed, which is consistent with data of Nakajima et al. [11]. These findings suggested that administration of Noni attenuated the impairment of cognitive function in the stressed mice. ...
The purpose of this study was to investigate effects of Morinda citrifolia fruit juice, which is locally called Noni, on stress-induced impairment of cognitive function. Male ICR mice were divided into four groups: Control (C mice), Restraint stress (RS mice), Restraint+Noni (Noni mice), and Restraint+vitamin E (VE mice). The RS, Noni, and VE mice were subjected to 8h of chronic restraint stress (CRS) 6days a week for 6weeks. During this period, the Noni and VE mice were given a diet supplemented with either Noni or vitamin E, respectively. At Week 5, the mice were subjected to the Morris water maze (MWM) test to measure cognitive function. At Week 7, mouse brains were isolated for immunohistochemical analysis with BrdU or CD31 antibody to assess the proliferation of new cells and blood vessel density in the dentate gyrus of the hippocampus. The time taken to reach the platform in the MWM test was shorter in the Noni mice than in the RS mice on Day 16. Malondialdehyde (MDA ) level of the Noni mice was significantly higher than that of the C mice; however no difference was found in MDA levels between the VE and C mice. Blood vessel area was significantly lower in the R and VE mice than in the C mice; no difference was found between the C and Noni mice. These findings suggest that the administration of Noni fruit juice protects brains from stress-induced impairment of cognitive function and that this protective effect may be related to improvement in stress-induced decreases in blood vessel density in the hippocampal dentate gyrus.
... 32 Several studies have demonstrated the effect of coated-melon SOD in ROSrelated diseases, such as cancer, cardiovascular disease, degenerative diseases, and infectious diseases. 33,[35][36][37] These studies have supported the oral administration of SOD as a complementary treatment for systemic diseases. 32,33,[35][36][37] Previous studies showed the effect of Mn-SOD extracted from B. amyloliquefaciens in a model of inflammatory bowel disease. ...
... 33,[35][36][37] These studies have supported the oral administration of SOD as a complementary treatment for systemic diseases. 32,33,[35][36][37] Previous studies showed the effect of Mn-SOD extracted from B. amyloliquefaciens in a model of inflammatory bowel disease. [23][24][25] The production of Bd-SOD could be more economical, since microbial suspension culture is a more convenient method for large-scale production by mass cultivation of cells than plant cultivation. ...
Purpose
We hypothesized that antioxidative enzymes supplementation could be a treatment option for dry eye. We investigated the efficacy of oral administration of Bacillus-derived superoxide dismutase (Bd-SOD) in a murine experimental dry eye (EDE).
Methods
In part I, mice were randomly assigned to normal control, EDE, and mice groups that were treated with oral Bd-SOD after induction of EDE (EDE + Bd-SOD group; four mice in each group). Expression of SOD2, a major antioxidant enzyme with manganese as a cofactor, was assessed by immunofluorescence staining. In part II, mice were divided into seven groups (six mice in each group): normal control, EDE, vehicle-treated, topical 0.05% cyclosporin A (CsA)-treated, and oral Bd-SOD-treated (2.5, 5.0, and 10.0 mg/kg Bd-SOD) groups. Tear volume, tear-film break-up time (TBUT), and corneal fluorescein-staining scores (CFS) were measured at zero, five, and 10 days after treatment. Ten days after treatment, 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate for reactive oxygen species (ROS), enzyme-linked immunosorbent for malondialdehyde, and TUNEL assays for corneal apoptosis, flow cytometry inflammatory T cells, and histological assessment were performed.
Results
Compared to the normal control group in part I, the EDE group showed significantly decreased SOD2 expression by immunofluorescence staining. However, the EDE + Bd-SOD group recovered similar to the normal control group. In part II, ROS, malondialdehyde, and corneal apoptosis were decreased in CsA and all Bd-SOD-treated groups. Corneal and conjunctival inflammatory T cells decreased, and conjunctival goblet cell density increased in CsA-treated and Bd-SOD–treated groups. Compared to the CsA-treated group, the 2.5 mg/kg Bd-SOD–treated group showed increased TBUT and decreased inflammatory T cells, and the 5.0 mg/kg Bd-SOD-treated group showed decreased CFS and increased conjunctival goblet cells.
Conclusions
Oral Bd-SOD administration might increase autogenous SOD2 expression in ocular surface tissue in EDE and could be developed as a complementary treatment for DE in the future.
... Previous studies have shown that the mice's regular cage (33 cm length, 22 cm height) was partitioned into six parts with aluminum boards to decrease the mice's physical activity (Nakajima et al., 2009(Nakajima et al., , 2010. For the present study, we made new cages to decrease the physical activity of the mice using acrylic plates and called the structure the physical inactivity FIGURE 1 | Measurement of the daily physical activity of mice using nano-tag apparatuses. ...
... Previous studies have suggested that hippocampal neuronal proliferation decreases are closely related to cognitive decline via aging (van Praag et al., 2005;Horowitz et al., 2020) or chronic stress (Nakajima et al., 2009;Muto et al., 2014;Lee et al., 2018). Furthermore, chronic stress causes a decrease in hippocampal blood vessel density, which leads to a depressive-like state (Kiuchi et al., 2012). ...
Regular exercise has already been established as a vital strategy for maintaining physical health via experimental results in humans and animals. In addition, numerous human studies have reported that physical inactivity is a primary factor that causes obesity, muscle atrophy, metabolic diseases, and deterioration in cognitive function and mental health. Regardless, an established animal experimental method to examine the effect of physical inactivity on physiological, biochemical, and neuroscientific parameters is yet to be reported. In this study, we made a new housing cage, named as the physical inactivity (PI) cage, to investigate the effect of physical inactivity on cognitive function and depressive-like states in mice and obtained the following experimental results by its use. We first compared the daily physical activity of mice housed in the PI and standard cages using the nano-tag method. The mice’s physical activity levels in the PI cage decreased to approximately half of that in the mice housed in the standard cage. Second, we examined whether housing in the PI cage affected plasma corticosterone concentration. The plasma corticosterone concentration did not alter before, 1 week, or 10 weeks after housing. Third, we investigated whether housing in the PI cage for 10 weeks affected cognitive function and depressive behavior. Housing in an inactive state caused a cognitive decline and depressive state in the mice without increasing body weight and plasma corticosterone. Finally, we examined the effect of regular low-intensity exercise on cognitive function and depressive state in the mice housed in the PI cage. Physical inactivity decreased neuronal cell proliferation, blood vessel density, and gene expressions of vascular endothelial growth factors and brain-derived neurotrophic factors in the hippocampus. In addition, regular low-intensity exercise, 30 min of treadmill running at a 5–15 m/min treadmill speed 3 days per week, prevented cognitive decline and the onset of a depressive-like state caused by physical inactivity. These results showed that our novel physical inactivity model, housing the mice in the PI cage, would be an adequate and valuable experimental method for examining the effect of physical inactivity on cognitive function and a depressive-like state.
... Studies have been conducted and data were collected from the animal experiments to clinical studies. (8) Since 2000, the melon extract with naturally fortified SOD has been developed as a food supplement. Due to the low pH and high proteolytic activity in the digestive system, however, the SOD will undergo structural changes and will become inactive, thus a single administration of SOD is considered less effective. ...
... Some studies claim that wheat gliadin protects the SOD from degradation process in the stomach. (8) Based on the previous studies, consumption of SOD supplements may provide a beneficial effect towards the diseases triggered by oxidative stress such as cardiovascular disease, cancer and infections, such as Feline Immunodeficiency Virus (FIV) that is homologous with Human Immunodeficiency Virus (HIV) virus. SOD oral supplementation may also indicate a significant increase in quality of life. ...
Background: Several various physiological functions in elderly people are diminished due to cell or tissue damage. One of the probable causes are oxidative stress yielded by free radicals.
Oxidative stress (ROS) induce lipid peroxidation in endothelial cell membrane, which generates atherosclerotic plaque. In a state of oxidative stress, MDA level will increased. The purpose of this study is to determine the effect of SOD supplementation on MDA, total cholesterol and LDL cholesterol plasma levels in the elderly.
Methods: This study was open label, a randomized control trial. Subjects were elderly people aged > 60 years (median 75, 60-82 ys, male 10 (24,4%)) institutionalized at Social Rehabilitation Unit Pucang Gading Semarang, Indonesia. The treatment group consisted of 16 people, received SOD (GlisodinR) 1 capsule (250 IU) 1 hour before meals, plus exercise scheduled for 8 weeks. The control group consisted of 15 people, received placebo, and exercise. Plasma MDA levels were examined using TBARS method, while total cholesterol and LDL cholesterol were examined using CHOD-PAP method.
Results: This study show a reduction of plasma MDA levels in the treatment group compare to control group ( p = 0.062 ). A significant reduction of total cholesterol and LDL cholesterol levels in the treatment group were found (before 190.00 and 131.47 g/dl, after 182.27 and 121.93 g/dl, p = 0.005 and 0.001).
Conclusion: The SOD supplementation significantly reduce Total Cholesterol and LDL level, but not MDA level in the elderly.
... The same research group later showed that 14 days pre-treatment with SOD/gliadin before aortic cross-clamping to simulate surgery, prevented the oxidative stress characteristics of ischaemia/reperfusion (Kick et al. 2007). A recent study using restraint-stressed mice showed that SOD/gliadin prevented stress-induced impairment of cognitive function, decreased lipid peroxidation and maintained neurogenesis in the hippocampus (Nakajima et al. 2009). Furthermore, a double-blind placebo-controlled study using SOD/gliadin in Metabolic Syndrome patients following the Lyon Heart Diet showed that intima medial thickening regressed over a 2-year period (Muth et al. 2004). ...
... The lack of an effect of the SOD/gliadin supplement is in contrast to previous studies that have shown positive benefits of an oral SOD supplement (Vouldoukis et al. 2004a;Muth et al. 2004;Cloarec et al. 2007). This includes protection against DNA damage following exposure to hyperbaric oxygen, (Muth et al. 2004) regression of carotid intima medial thickening in metabolic syndrome subjects (Cloarec et al. 2007), prevention of oxidative stress following ischaemia/reperfusion (Kick 2000) and prevention of stress-induced impairment of cognitive function (Nakajima et al. 2009). The dosage used in these studies was equivalent to that used in our study. ...
Fatigue syndromes exist on a continuum of severity from mild and transient to the disabling chronic fatigue syndrome, with oxidative stress linked to its pathogenesis. A thermolabile gliadin-combined plant superoxide dismutase (SOD) extract has shown potential in clinical trials as a therapeutic antioxidant. This study investigated the effects of 12 weeks of 500 mg/day of a SOD/gliadin supplement on fatigue. Thirty-eight women aged 50-65 years with self-perceived fatigue entered this randomized, double-blind, placebo-controlled trial. The primary outcome measure was general fatigue determined by the Multidimensional Fatigue Inventory (MFI). Secondary outcome measures included other measures of fatigue from the MFI and blood measures of oxidative stress, antioxidant status and hormones. There were no significant (P>0.05) differences between, or within groups, for decreases in general fatigue (active=1.6%, placebo=4.1%). There were no within or between group differences (P>0.05) in other measures of fatigue (physical fatigue, reduced activity, reduced motivation, mental fatigue and total fatigue score). In regard to the biochemical measures, there were non-significant (P>0.05) differences in increases in plasma SOD activity (active=7.1%, placebo=12.2%), plasma GPx activity (active=2.4%, placebo=0.7%), red blood cell GPx activity (active=9.8%, placebo=4.4%). Markers of oxidative stress were decreased but there were no differences (P>0.05) within or between groups; malondialdehyde (active=4.1%, placebo=1.6%), F-2 isoprostanes (active=14.7%, placebo=22.4%). There was a trend (P=0.08) for a decrease in cortisol in the active group (24.6%), however this was not significantly different from the decrease in the placebo participants (4.1%). DHEA differences were not significant (P<0.05) and declined 1.3% in the active group and 14.4% in the placebo group. In summary, the thermolabile SOD/gliadin supplement had no significant effect on self-perceived fatigue, antioxidants, oxidative stress or hormones in women aged 50-65 years.
... In line with our results, numerous studies have demonstrated how combinations of antioxidant (ALA and Resveratrol) and neurotrophic (LAC) agents can contribute to pain control, reducing the use of analgesic drugs and improving the safety profile of the treatments used [30][31][32][33]. ...
Background and Objectives: In the Western world, back pain and sciatica are among the main causes of disability and absence from work with significant personal, social, and economic costs. This prospective observational study aims to evaluate the effectiveness of a rehabilitation program combined with the administration of Alpha Lipoic Acid, Acetyl-L-Carnitine, Resveratrol, and Cholecalciferol in the treatment of sciatica due to herniated discs in young patients in terms of pain resolution, postural alterations, taking painkillers, and quality of life. Materials and Methods: A prospective observational study was conducted on 128 patients with sciatica. We divided the sample into 3 groups: the Combo group, which received a combination of rehabilitation protocol and daily therapy with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol for 30 days; the Reha group, which received only a rehabilitation protocol; and the Supplement group, which received only oral supplementation with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol. Clinical assessments were made at the time of recruitment (T0), 30 days after the start of treatment (T1), and 60 days after the end of treatment (T2). The rating scales were as follows: the Numeric Rating Scale (NRS); the Oswestry Disability Questionnaire (ODQ); and the 36-item Short Form Health Survey (SF-36). All patients also underwent an instrumental stabilometric evaluation. Results: At T1, the Combo group showed statistically superior results compared to the other groups for pain (p < 0.05), disability (p < 0.05), and quality of life (p < 0.05). At T2, the Combo group showed statistically superior results compared to the other groups only for pain (p < 0.05) and quality of life (p < 0.05). From the analysis of the stabilometric evaluation data, we only observed a statistically significant improvement at T2 in the Combo group for the average X (p < 0.05) compared to the other groups. Conclusions: The combined treatment of rehabilitation and supplements with anti-inflammatory, pain-relieving, and antioxidant action is effective in the treatment of sciatica and can be useful in improving postural stability.
... Glisodin® extract has been administered to animals and humans in various studies with no adverse side effects. Studies have been conducted on cancer, cardiovascular, degenerative, and infectious diseases (Webb, Lehman and McCord, 2008;Nakajima et al., 2009;Carillon et al., 2013;Porfire et al., 2014;Romao, 2015;Subandrate, Safyudin, Mutmainah Arifin and Oktalisa, 2015;Ahasan et al., 2019). These diseases are related to ROS production, a condition improved by manipulating antioxidant levels. ...
Sepsis is a major cause of death in intensive care units whose development is supported by an imbalance of oxidative stress and antioxidant. Superoxide dismutase (SOD) is a primer endogen antioxidant that prevents reactive oxygen species (ROS). Extensive studies on animals and humans have examined Cucumis melo L.C, a cantaloupe rich in SOD, and its combination with gliadin. The studies aimed to determine the effect of enteral administration of Cucumis melo L.C. gliadin (CME-gliadin) 28 days before inducing sepsis in rats. This experimental study aimed to compare four groups of male Wistar rats, including negative and positive control rats and those supplemented with SOD CME-gliadin 1 IU/day and SOD CME-gliadin 5 IU/day. All rats were given the same standard, except the supplementation for 28 days. Sepsis was induced by intraperitoneal injection of LPS 10 mg/kg. Enteral administration of SOD – gliadin extract of CME-gliadin for 28 days was used as antioxidant prophylaxis against oxidative stress due to sepsis. The results showed that enteral administration of CME-gliadin of 1 IU/day and 5 IU/day significantly increased SOD levels based on examination after 14 and 28 days. Also, it significantly decreased MDA (p < 0.001), TNF-α (p < 0.001), and lactate levels in rats induced by sepsis. However, the increase in lactate levels was above >1.64 mmol/l, indicating a high mortality rate. There was no significant difference in SOD, MDA, TNF-α, and Lactate levels between SOD 1 IU and SOD 5 IU. This descriptive data show that SOD 5 IU has a better result in MDA, TNF-α, and Lactate levels than SOD 1 IU.
... The divided cages used in the present study were created to suppress the mice's daily physical activity by subdividing a standard mouse cage into six compartments using plastic boards 42,43 . We used a Western diet (F2WTD) as an HFD and a standard diet as per a Western diet (F-93G-MC). ...
Obesity is a risk factor for development of metabolic diseases and cognitive decline; therefore, obesity prevention is of paramount importance. Neuronal mitochondrial dysfunction induced by oxidative stress is an important mechanism underlying cognitive decline. Olive leaf extract contains large amounts of oleanolic acid, a transmembrane G protein-coupled receptor 5 (TGR5) agonist, and oleuropein, an antioxidant. Activation of TGR5 results in enhanced mitochondrial biogenesis, which suggests that olive leaf extract may help prevent cognitive decline through its mitochondrial and antioxidant effects. Therefore, we investigated olive leaf extract’s effects on obesity, cognitive decline, depression, and endurance exercise capacity in a mouse model. In physically inactive mice fed a high-fat diet, olive leaf extract administration suppressed increases in fat mass and body weight and prevented cognitive declines, specifically decreased working memory and depressive behaviors. Additionally, olive leaf extract increased endurance exercise capacity under atmospheric and hypoxic conditions. Our study suggests that these promising effects may be related to oleanolic acid’s improvement of mitochondrial function and oleuropein’s increase of antioxidant capacity.
... The extract of oral melon SOD delivers to the brain stimulate to inhibit stress -induced impairment of spatial memo ry [25]. Similar trends have been observed by dietary turmeric on lipid per-o xidation (iron-induced) on rat liver showing lowering of level by elevation of super oxide dismutase enzyme, catalases and glutathione peroxidases. ...
In many human maladies there is a disproportion at reactive oxygen species (ROS) generation and its defense via antioxidant. This imbalance is minimized by means of superoxide dismutase (SOD); a significant antioxidant enzyme to control oxidative stress by conversion of free radical (O-2) into hydrogen peroxide and oxygen, which is, further transformed into water using peroxidases and catalase. The minimization of free radicals or ROS could be one of the effective strategies against free radical related human malady. But the issue is that bioavailability of SODs is limited. Various natural SOD sources like plants, microorganisms and animals have been extensively explored. To boost up the bioavailability of SOD, few therapeutic implications must be developed. This review is about the gathering of information about the current possible therapeutic applications with respect to SOD to increase their bioavailability and reduce the free radical level to alter cellular function.
... The extract of oral melon SOD delivers to the brain stimulate to inhibit stress -induced impairment of spatial memo ry [25]. Similar trends have been observed by dietary turmeric on lipid per-o xidation (iron-induced) on rat liver showing lowering of level by elevation of super oxide dismutase enzyme, catalases and glutathione peroxidases. ...
... For these reasons, natural enzymes capable of detoxifying ROS, such as the superoxide dismutase (SOD) family converting superoxide anion to hydrogen peroxide and catalase converting H 2 O 2 to water, have been considered as potential antioxidant drugs. 13 However, those applications have been limited by their lack of stability and loss of activation in harsh environments (e.g., nonphysiological pH, high temperature, or in the presence of inhibitors). 14 In contrast, artificial enzymes created from nanomaterials (nanoenzymes) exhibit high stability, are inexpensive, and can be developed easily. ...
In order to develop nanomaterials as artificial enzymes, it is necessary to better understand how their physicochemical properties affect their enzyme-like activities. Although prior research has demonstrated that nanomaterials exhibit tunable enzyme-like activities depending on their size, structure, and composition, few studies have examined the effect of surface facets, which determine surface energy or surface reactivity. Here, we use electron spin-resonance (ESR) spectroscopy to report that lower-surface-energy {111}-faceted Pd octahedrons have greater intrinsic antioxidant enzyme-like activity than higher-surface-energy {100}-faceted Pd nanocubes. Our in vitro experiments found that those same Pd octahedrons are more effective than Pd nanocubes at scavenging reactive oxygen species (ROS). Those reductions in ROS preserve the homogeneity of mitochondrial membrane potential and attenuate damage to important biomolecules, thereby allowing a substantially higher number of cells to survive oxidative challenges. Our computations of molecular mechanisms for the antioxidant activities of {111} and {100}-faceted Pd nanocrystals, as well as their activity order, agree well with experimental observations. These findings can guide the design of antioxidant-mimicking nanomaterials, which could have therapeutic or preventative potential against oxidative stress related diseases.
... Among the main ingredients of the Supplement are an SOD-rich melon concentrate, yeast, mushrooms and omega-3 fatty acids. The SOD-rich melon concentrate was selected based on reports of improved anti-oxidant status [42,50,51]. As discussed above, the results of supplementing SODrich melon concentrate to horses has produced mixed results, with indications of potential for increased oxidative status and reducing inflammation. ...
This study determined the ability of an oral nutraceutical supplement to attenuate the oxidative stress and inflammation that occurs in muscles and joints with repeated bouts of high intensity exercise in horses. The supplement, fed daily, was comprised of whole dried mushrooms, golden flaxseed, omega-3 fatty acids, plant-based enzymes, a melon concentrate powder and Saccharomyces cerevisiae boulardii. Ten horses participated in a partial cross-over design, with 7 horses completing the Control trial and 7 horses completing the Supplement trial. Blood and synovial fluid samples (from the intercarpal joint) were taken before, and at 1 and 24 hours after a standardized, repeated high intensity exercise test that was performed before supplementation and on the 22nd day of supplementation. At the end of the Supplement trial exercise resulted in reduced concentrations of plasma markers of oxidative stress (decreased TBARS, with increased total antioxidant status and increased superoxide dismutase activity); there was no effect on plasma markers of muscle injury (creatine, CK, AST) or inflammation (PGE2, nitric oxide). Within synovial fluid, there was a tendency for increased superoxide dismutase activity, and decreased concentration of glycosaminoglycans. It is concluded that the Supplement, when fed to horses as part of the normal diet for 23 days, was associated with reduced concentrations of markers of oxidative stress and inflammation in muscle and synovial fluid.
... Copyright: © 2016 Houldsworth extracted from melons and combined with gliadin. When mice received this it was found to promote antioxidant defenses in the brain and to prevent stress induced impairment of memory and in other animal studies, it was concluded that supplementation with gliadin-combined standardized melon SOD extract (Glisodin) promoted the cellular antioxidant status and protected against oxidative stress-induced cell death [45,46]. No concrete conclusions have been made about the health benefits of human SOD-2 supplementation and studies thus far all state that much larger studies are needed [47]. ...
A review of the antioxidant gene manganese Superoxide
Dismutase (SOD-2) and its association with disease processes,
especially Diabetes Mellitus (DM) and diabetic complications. The
endogenous antioxidant enzyme systems, such as observed with
Superoxide Dismutase (SOD), helps to manage the levels of Reactive
Oxygen Species (ROS) in a cell that are generated by the cell’s
respiratory reactions. The role of free radical reactions in protein
oxidation, DNA damage and lipid peroxidation is strongly debated in
relation to human disease and has been implicated in many disease
states.
... Several groups demonstrated positive effects of SODs administration on nervous tissue damage and brain functions. Oral administration of SODs has been shown to improve cognitive functions, such as memory, learning and concentration both in mice [233] and in humans [234]. Moreover, also SODs mimetics and SOD-overexpressed models have been developed in order to better understand SODs effects and their mechanisms of action [reviewed in 235]. ...
Neurodegenerative diseases are characterized by a gradual and selective loss of neurons. ROS overload has been proved to occur early in this heterogeneous group of disorders, indicating oxidative stress as a primer factor underlying their pathogenesis. Given the importance of a better knowledge of the cause/effect of oxidative stress in the pathogenesis and evolution of neurodegeneration, recent efforts have been focused on the identification and determination of stable markers that may reflect systemic oxidative stress. This review provides an overview of these systemic redox biomarkers and their responsiveness to antioxidant therapies. Redox biomarkers can be classified as molecules that are modified by interactions with ROS in the microenvironment and antioxidant molecules that change in response to increased oxidative stress. DNA, lipids (including phospholipids), proteins and carbohydrates are examples of molecules that can be modified by excessive ROS in vivo. Some modifications have direct effects on molecule functions (e.g. to inhibit enzyme function), but others merely reflect the degree of oxidative stress in the local environment. Testing of redox biomarkers in neurodegenerative diseases has 3 important goals: 1) to confirm the presence or absence of systemic oxidative stress; 2) to identify possible underlying (and potentially reversible) causes of neurodegeneration; and 3) to estimate the severity of the disease and the risk of progression. Reflecting pathological processes occurring in the whole body, redox biomarkers may pinpoint novel therapeutic targets and lead to diagnose diseases before they are clinically evident.
... Furthermore, SOD inhibits biosynthesis of some principal inflammatory cytokines and avoids apoptosis of nerves [26]. Since during inflammationwhether acute or chronic-endogenous SOD is not sufficient to completely neutralize oxygen free radicals, dietary supplementation of SOD has been investigated in some diseases, such as arthritis [27], and it has been shown that orally administered SOD not only has antioxidant activity but also works as an effective nerve protector [28,29]. ...
Since oxidative stress plays a pathogenetic role in chronic neck pain (CNP), we investigated whether a combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) might improve pain control and the efficacy of physiotherapy ("multimodal therapy") in patients with CNP.
This study was conducted in the Rehabilitation Unit of the Department of Surgical and Oncological Sciences at the University Policlinic in Palermo, Italy.
This was a prospective, randomized, open study in outpatients.
Patients randomly received either physiotherapy alone (group 2; n = 45) or a combination of ALA 600 mg and SOD 140 IU daily in addition to physiotherapy (group 1; n = 51), for 60 days. Pain was assessed by a visual analogue scale (VAS) and a modified Neck Pain Questionnaire (mNPQ). Treatment compliance and safety were also evaluated.
Both groups experienced a significant reduction in the VAS and mNPQ scores after 1 month; however, while no further improvement was observed in group 2 at 60 days, group 1 showed a further VAS reduction (p < 0.001). In addition, in the mNPQ at 60 days, more patients in group 1 than in group 2 reported that their neck pain was improved (p < 0.01), and they showed greater compliance with prescribed physiotherapy (p = 0.048). No drug reaction was observed.
Use of ALA/SOD in combination with physiotherapy may be a useful approach to CNP, being antioxidants that act on nerve inflammation and disease progression.
These preliminary observations suggest that some interesting goals (better pain control and physical wellbeing) can be achieved by multimodal therapy in CNP patients.
... The C and TD mice were housed in standard mouse cages with five mice per cage. The TD+CUS, TD+CUS+ME and TD+CUS+IE mice were housed in standard mouse cages divided into six cells to reduce their living space and to decrease their daily activity [17]. The TD, TD+CUS, TD+CUS+ME and TD+CUS+IE mice were fed a tryptophandeficient (TD) powered diet (Oriental Yeast Co., Ltd., Japan). ...
Regular exercise has an antidepressant effect in human subjects. Studies using animals have suggested that the antidepressant effect of exercise is attributable to an increase of brain 5-hydroxytryptamine (5-HT); however, the precise mechanism underlying the antidepressant action via exercise is unclear. In contrast, the effect of 5-HT on antidepressant activity has not been clarified, in part because the therapeutic response to antidepressant drugs has a time lag in spite of the rapid increase of brain 5-HT upon administration of these drugs. This study was designed to investigate the contribution of brain 5-HT to the antidepressant effect of exercise. Mice were fed a tryptophan-deficient diet and stressed using chronic unpredictable stress (CUS) for 4 weeks with or without the performance of either moderate or intense exercise on a treadmill 3 days per week. The findings demonstrated that the onset of depression-like behavior is attributable not to chronic reduction of 5-HT but to chronic stress. Regular exercise, whether moderate or intense, prevents depression-like behavior with an improvement of adult hippocampal cell proliferation and survival and without the recovery of 5-HT. Concomitantly, the mice that exercised showed increased hippocampal noradrenaline. Regular exercise prevents the impairment of not long-term memory but short-term memory in a 5-HT-reduced state. Together, these findings suggest that: (1) chronic reduction of brain 5-HT may not contribute to the onset of depression-like behavior; (2) regular exercise, whether moderate or intense, prevents the onset of chronic stress-induced depression-like behavior independent of brain 5-HT and dependent on brain adrenaline; and (3) regular exercise prevents chronic tryptophan reduction-induced impairment of not long-term but short-term memory.
... It was shown that the SOD deficiency could reduce adult hippocampal neurogenesis in the brain (Yoo et al., 2012). While, SOD supplementation prevents stress-induced impairments of cognitive function and maintains neurogenesis in the hippocampus through antioxidant activity (Nakajima et al., 2009). On the other hand, Lynn et al. (2005) showed neuronal abnormalities and inadequate stress response in SOD mutant mice. ...
This study aimed to explore the relationship between antioxidant enzyme activities and neurological soft signs (NSS) in a sample of patients with schizophrenia. Sixty clinically stable patients with schizophrenia treated mostly by first-generation antipsychotics and 30 matched healthy controls were recruited. NSS were assessed in two groups by a standardized neurological examination (Krebs et al., 2000). The red blood cell (RBC) antioxidant activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were measured by spectrophotometry. RBC activities of all enzymes studied: SOD, GSH-Px and CAT, were significantly lower in the patients compared to control group. All NSS scores were significantly higher in the patients compared to healthy controls' scores. In the patients, a negative correlation was found between RBC SOD activity and NSS total score and motor coordination and motor integration sub-scores. The association between low SOD activity as a marker of oxidative stress and NSS in schizophrenic patients suggests a common pathological process of these abnormalities.
... In addition, this SOD-gliadin complex has been shown to • Inhibit oxidative stress (Albicini et al., 2005;Nakajima et al., 2009;Vouldoukis et al., 2004) • Inhibit ultraviolet oxidative stress (Mac-Mary, Sainthillier, Courderotmasuyer, Creidi, & Humbert, 2007) • Promote immune modulation (Okada et al., 2006) • Inhibit vascular inflammation Results of a few studies (Arent, DiFabio, Greenwood, Pellegrino, & Williams, 2005;Hong, Hong, Chang, & Cho, 2004) suggested that the melon extract (Cucumis melo LC) may attenuate peroxidative and inflammatory response to exercise in athletes. ...
The aim of this study was to investigate the effect of plant superoxide dismutase extract (GliSODin) supplementation on the balance of oxidants and antioxidants in the serum and erythrocytes of competitive rowers. The double-blinded study included 19 members of the Polish rowing team who were participating in a preparatory camp. Subjects were randomly assigned to the supplemented group (n = 10), who received 2 capsules (500 mg) of GliSODin extract once daily for 6 weeks, or the placebo group (n = 9). At the beginning and end of the study, subjects performed a 2,000-m maximum-effort test on a rowing ergometer. Blood samples were taken from the antecubital vein before each exercise test, 1 min after completing the test, and after a 24-hr restitution period. The following redox parameters were assessed in erythrocytes: superoxide dismutase (SOD) activity, glutathione peroxidase activity, and concentrations of thiobarbituric-acid-reactive substances. In addition, creatine kinase activity and total antioxidant capacity were measured in plasma samples, lactate levels were determined in capillary blood samples, and C-reactive protein and lactate dehydrogenase concentrations were measured in serum. After supplementation, SOD activity was significantly higher (p = .0037) in the supplemented group than the placebo group, and C-reactive protein was significantly (p = .00001) lower in athletes receiving GliSODin than those in the placebo group. In conclusion, supplementation with an extract rich in SOD activity promoted antioxidant status and protected against increased inflammation in the serum of professional rowers but had no effect on oxidative damage induced by exhaustive exercise.
... In addition, an age-dependent decrease in serotonin metabolite (5-HIAA) levels was observed in the hippocampus and dorsal raphe nucleus of these animals (Silva et al. 2007). The behavioural test used to assess the spatial cognitive aspects in that study and in many others (Li et al. 2009; Nakajima et al. 2009; Topic et al. 2005) was the Morris water maze (MWM), which is a task that can be considered aversive. One question that can be raised is whether an emotional component could, to some extension, explain the cognitive deficit observed. ...
Emotion and spatial cognitive aspects were assessed in adult and middle-aged rats using the elevated T-maze (ETM) and the Morris water maze (MWM) tasks. Both adult and middle-aged rats were able to acquire inhibitory avoidance behaviour, though the middle-aged subjects showed larger latencies along the trials, including the baseline, which was significantly longer than that showed by adult rats. Further, compared to adult rats, middle-aged rats had longer escape latency. In spite of the worse performance in the second session of the spatial cognitive task, the middle-aged rats were able to learn the task and remember the information along the whole probe trial test. Both thalamic serotonin (5-HT) concentration and amygdala serotonergic activity (5-HIAA/5-HT) are significantly correlated, respectively, to escape latency and behavioural extinction in the MWM only for middle-aged rats. A significant correlation between the 5-HIAA/5-HT ratio in the amygdala and behavioural extinction for middle-aged, but not for adult, rats was observed. This result suggests that serotonergic activity in the amygdala may regulate behavioural flexibility in aged animals. In addition, a significant negative correlation was found between hippocampal 5-HIAA/5-HT ratio and the path length at the second training session of the MWM task, although only for adult subjects. This was the only session where a significant difference between the performance of middle-aged and adult rats has occurred. Although the involvement of the hippocampus in learning and memory is well established, the present work shows, for the first time, a correlation between a serotonergic hippocampal parameter and performance of a spatial task, which is lost with ageing.
Cyclophosphamide (CYL) is a first-line cancer chemotherapeutic agent widely used for the treatment of cancer that has severe toxic effects. The primary mechanism by which CYL induces toxicity through free radical generation. Morinda citrifolia (Noni) fruit juice is an herbal remedy documented to have antioxidant properties. The aim of the current study was to investigate the protective effect of noni against CYL-induced memory impairment in Swiss albino mice. Treatment schedule: Group 1: Normal: Received vehicle; Group 2: CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one; Group 3: NJ treatment: Received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 4: DNG treatment: DNG (360 mg/b.w. p.o.) once daily for 14 days, Group 5: NJ + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour of received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 6: DNG + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour received DNG (360 mg/b.w. p.o.) once daily for 14 days. Mice were subjected to the Morris water maze (MWM) challenge for two weeks as part of a behavioral study. Short-term memory impairment was observed in the behavioral activity of CYL-treated mice in the MWM test in the 1st week trial, and this effect was reversed in the 2nd week trial in the combination treatment group. The behavioral analysis proved that noni supplementation reduced the risk of memory impairment caused by CYL. Biochemical analysis revealed that CYL markedly increased the levels of AChE and MDA in brain tissue. Similarly, decreases in the levels of antioxidants, i.e., GSH, CAT, SOD and GST, were detected in the brain tissue of the mice exposed to CYL. Qualitative and quantitative examinations of histopathological examination of the mouse hippocampus supported the above findings. The results demonstrated that noni supplement therapy reversed the changes in the MDA, AChE, and antioxidant enzyme levels while improving the behavioral and histological alterations caused by CYL. Long-term hippocampal growth and memory are unaffected, suggesting that CYL is less harmful. According to our research, supplementing with noni in conjunction with CYL may be a helpful treatment strategy for treating memory impairment caused by CYL.
Background
This study examines the associations of plasma superoxide dismutase (SOD) activity, an indicator of oxidative stress, with disability in activities of daily living (ADL) and objective physical functioning among Chinese older adults.
Methods
We used cross-sectional data of 2223 older adults (≥65 years, including 1505 adults≥80 years) from the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study. Plasma SOD activity was assessed by the T-SOD assay kit based on the hydroxylamine method. Outcomes included ADL disability and disability in three objective physical tasks (standing up from a chair, picking up a book from the floor, and turning around 360°). Logistic regression models were used to examine the associations of plasma SOD activity with outcomes.
Results
After controlling for age and sex, compared with participants in the lowest quartile group of SOD activity, those in the highest quartile group had 31% lower odds of ADL disability (odds ratio [OR]: 0.69; 95%CI: 0.48, 0.98); 60% lower odds of disability in standing up from a chair (OR: 0.40; 95%CI: 0.25, 0.63); and 57% lower odds of disability in picking up a book from a floor (OR: 0.43; 95%CI: 0.28, 0.65). The results did not change substantially after controlling for additional covariates. We did not observe statistically significant age and sex differences.
Conclusions
Overall, plasma SOD activity was associated with subjectively and objectively measured disability in Chinese older adults, highlighting the potential of SOD activity to serve as a biomarker of physical functioning.
Oxidative stress in cells caused by the accumulation of reactive oxygen species (ROS) is a common cause of cell function degeneration, cell death and various diseases. Efficient, robust and inexpensive nanoparticles (nanoenzymes) capable of scavenging/detoxifying ROS even in harsh environments are attracting strong interest. Prussian blue analogues (PBAs), a prominent group of metalorganic nanoparticles (NPs) with the same cyanometalate structure as the traditional and commonly used Prussian blue (PB), has long been envisaged to mimic enzyme activities for ROS scavenging. However, their biological toxicity, especially potential effects on living beings in practical applications, have not yet been fully understood. Here we reveal the enzyme-like activity of the FeCo-PBA NPs and investigate the effects of the FeCo-PBA on the cell viability and growth. We elucidate the nanoenzyme effect on the ethanol-production efficacy of a typical model organism, the engineered industrial strain Saccharomyces cerevisiae. We further demonstarte that the FeCo-PBA NPs are not toxic to the cells over a broad dose range (0-100 μg/mL), while clearly boosting the yeast fermentation efficiency by mitigationg oxidative stress. The atmospheric pressure cold plasma (APCP) pretreatment is used as a multifunctional environmental stress produced by the plasma reactive species. While the plasma enhances the NP cellular uptake, the FeCo-PBA NPs protect the cells from the oxidative stress induced by both the plasma and the fermentation processes. This synegistic effect leads to the higher secondary metabolite yields and energy production. Collectively, this study confirms the positive effects of PBA nanoparticles in living cells through ROS scavenging, thus potentially opening new ways to control cellular machinery in the future nano-biotechnology and nano-biomedical applications.
El envejecimiento se caracteriza por cambios progresivos en los tejidos que dan lugar a la disminución de la función y, finalmente, a la muerte. A lo largo de los años se han descrito múltiples teorías tratando de explicar por qué se produce el envejecimiento. Una de las más aceptadas es la teoría de los radicales libres, la cual sugiere que las especies reactivas del oxígeno forman productos endógenos al reaccionar con otras moléculas, y que estas juegan un papel importante en el envejecimiento. Las células y los órganos del cuerpo tienen sistemas antioxidantes, los cuales pueden ser enzimáticos, no enzimáticos o proteínas de unión. Todos actúan sinérgicamente para neutralizar las diferentes especies reactivas del oxígeno, formando una red de antioxidantes que retrasan el proceso de envejecimiento.
It is well known that regular low or mild exercise helps to improve and maintain cognition. On the other hand, ever thought many people prefer high-intensity exercise (e.g., running, swimming, biking, soccer, basketball, etc.) to get rid of stress or improve their health, the previous studies reported that intense exercise either impairs cognition or has no effect on cognitive function. However, we previously showed that intermittent intense exercise prevents stress-induced depressive behavior in mice in a similar manner to moderate exercise. On the basis of this finding, we investigated the effect of intermittent intense exercise on cognitive deficit in chronically stressed mice. A total of forty mice were evenly divided into control, stressed, stressed with moderate exercise, and stressed with intense exercise groups. The stressed mice were chronically exposed a restraint stress (10 h/day, 6 days/week for 7 weeks). The exercised mice were subjected to intermittent intense or endurance moderate running on the treadmill three times a week. Cognition was evaluated using the Morris water maze test and the object recognition test. Chronic stress decreased cognition, and newborn cell survival and blood vessel density in the hippocampus. However, both regular intense and moderate exercise prevented decrease of cognition, improved newborn cell survival and blood vessel density. These findings suggest that intermittent intense exercise may protect against decrease of cognition in a similar manner to moderate exercise and that both exercise-induced protection of decrease of cognition is closely related to newborn cell survival and angiogenesis in the hippocampus.
Background:
Neuropathic mechanisms largely contribute to low back pain (LBP) and oxidative stress is acknowledged as one of the causes of nerve damage typical of neuropathic pain: antioxidant agents may be a useful choice in the multimodal treatment strategy for chronic LBP patients.
Aim:
The aim of this study was to detect changes in perceived pain, functional activity and in the assumption of analgesics in patients with chronic LBP treated with a combination of alpha-lipoic acid (ALA) and superoxide dismutase (SOD).
Design:
Prospective non-randomized open-label study.
Setting:
Outpatient at TAMMEF (Therapeutic Application of Musically Modulated Electromagnetic Fields) Centre of the University of Siena.
Population:
The study enrolled 98 adult patients with chronic (≥12 weeks) LBP with or without radiculopathy and without neoplastic or inflammatory pathologies.
Methods:
Patients were treated for 60 days with 600 mg ALA and 140 UI SOD/die. The Roland Morris Disability Questionnaire and Pain Rating Scale were used and concomitant use of medications (with particular attention to analgesics) and adverse events (toxicity) were recorded during treatment. Differences between all the study time points were calculated for the scores of the two tools and for the need of concomitant treatment with analgesics.
Results:
At the end of the study only 8% of patients still used analgesics versus 73.5% registered at baseline (P<0.01). Regarding self-reported tools, a statistically significant improvement both for perceived pain and functional disabilities occurred: pain ameliorated after 40 days of therapy and the improvement was significant both statistically (P<0.05) and clinically. Only 4 patients stopped the treatment due to unacceptable pain (not related to the treatment).
Conclusion:
Oral treatment with ALA and SOD improves functionality and reduces the use of analgesics in chronic LBP patients.
Clinical rehabilitation impact:
Oral combination of ALA and SOD may be a powerful adjuvant in multimodal therapy of chronic LBP patients.
Oxidative stress, involved in many diseases, is defined as an impaired balance between reactive oxygen species (ROS) production and antioxidant defences. Antioxidant enzymes such as superoxide dismutase (SOD) play a key role in diminishing oxidative stress. Thus, the removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. The poor bioavailability of exogenous SODs has been criticized. However, improvements in SOD formulation may overcome this limitation and boost interest in its therapeutic properties. Here, we provide a review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value. Protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration has also been reported to alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders, raising the question of its mechanism of action in these diverse situations. Some authors have shown an increase in endogenous antioxidant enzymes after exogenous SODs administration. The induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress, could explain all the effects observed. Further investigations need to be carried out to test the hypothesis that SODs supplementation acts by inducing an endogenous antioxidant defence.
The effects of grape seed extract (GSE), a major source of phenolic compounds, were examined on cell proliferation, neuroblast differentiation and integration into granule cells in the hippocampal dentate gyrus (DG) of middle-aged (12 month-old) mice using Ki67, doublecortin (DCX) immunohistochemistry and 5'-bromo-2-deoxyguanosine (BrdU)/calbindin D-28k (CB) double immunofluorescence study, respectively. GSE (25, 50 and 100 mg/kg) was administered orally for 28 days, and the animals were treated with 50 mg/kg BrdU intraperitoneally on the day of first GSE treatment. In the vehicle-treated group, Ki67 and DCX immunoreactivity was detected in the subgranular zone of the DG (SZDG). GSE treatment dose-dependently increased the number of Ki67 and DCX immunoreactive cells, particularly the number of DCX immunoreactive neuroblasts with well-developed (tertiary) dendrites. GSE also dose-dependently increased DCX protein levels. In addition, GSE treatment increased significantly the number of BrdU/CB double labeled granule cells. These results suggest that GSE significantly increases cell proliferation, neuroblast differentiation and integration into granule cells in the DG, and the consumption of GSE enhances the plasticity of hippocampus in middle-aged mice.
Chronic stress impairs cognitive function and hippocampal neurogenesis. This impairment is attributed to increases in oxidative stress, which result in the accumulation of lipid peroxide. On the other hand, voluntary exercise enhances cognitive function, hippocampal neurogenesis, and antioxidant capacity in normal animals. However, the effects of voluntary exercise on cognitive function, neurogenesis, and antioxidants in stressed mice are unclear. This study was designed to investigate whether voluntary exercise cures stress-induced impairment of cognitive function accompanied by improvement of hippocampal neurogenesis and increases in antioxidant capacity. Stressed mice were exposed to chronic restraint stress (CRS), which consisted of 12h immobilization daily and feeding in a small cage, for 8 weeks. Exercised mice were allowed free access to a running wheel during their exposure to CRS. At the 6th week, cognitive function was examined using the Morris water maze (MWM) test. Daily voluntary exercise restored stress-induced impairment of cognitive function and the hippocampal cell proliferation of newborn cells but not cell survival. Voluntary exercise increased insulin-like growth factor 1 (IGF-1) protein and mRNA expression in the cerebral cortex and liver, respectively. In addition, CRS resulted in a significant increase in the number of 4-hydrosynonenal (4-HNE)-positive cells in the hippocampal dentate gyrus; whereas, voluntary exercise inhibited it and enhanced glutathione s-transferases (GST) activity in the brain. These findings suggest that voluntary exercise attenuated the stress-induced impairment of cognitive function accompanied by improvement of cell proliferation in the dentate gyrus. This exercise-induced improvement was attributed to exercise-induced enhancement of IGF-1 protein and GST activity in the brain.
The potential benefits to health of antioxidant enzymes supplied either through dietary intake or supplementation is still a matter of controversy. The development of dietary delivery systems using wheat gliadin biopolymers as a natural carrier represents a new alternative. Combination of antioxidant enzymes with this natural carrier not only delayed their degradation (i.e. the superoxide dismutase, SOD) during the gastrointestinal digestive process, but also promoted, in vivo, the cellular defences by strengthening the antioxidant status. The effects of supplementation for 28 days with a standardized melon SOD extract either combined (Glisodin®) or not with gliadin, were evaluated on various oxidative-stress biomarkers. As already described there was no change either in superoxide dismutase, catalase or glutathione peroxidase activities in blood circulation or in the liver following non-protected SOD supplementation. However, animals supplemented with Glisodin® showed a significant elevation in circulated antioxidant enzymes activities, correlated with an increased resistance of red blood cells to oxidative stress-induced hemolysis. In the presence of Sin-1, a chemical donor of peroxynitrites, mitochondria from hepatocytes regularly underwent membrane depolarization as the primary biological event of the apoptosis cascade. Hepatocytes isolated from animals supplemented with Glisodin® presented a delayed depolarization response and an enhanced resistance to oxidative stress-induced apoptosis. It is concluded that supplementation with gliadin-combined standardized melon SOD extract (Glisodin®) promoted the cellular antioxidant status and protected against oxidative stress-induced cell death. Copyright © 2004 John Wiley & Sons, Ltd.
The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 569–578, 1999
Lipid peroxidation often occurs in response to oxidative stress, and a great diversity of aldehydes are formed when lipid hydroperoxides break down in biological systems. Some of these aldehydes are highly reactive and may be considered as second toxic messengers which disseminate and augment initial free radical events. The aldehydes most intensively studied so far are 4-hydroxynonenal, 4-hydroxyhexenal, and malonaldehyde. The purpose of this review is to provide a comprehensive summary on the chemical properties of these aldehydes, the mechanisms of their formation and their occurrence in biological systems and methods for their determination. We will also review the reactions of 4-hydroxyalkenals and malonaldehyde with biomolecules (amino acids, proteins, nucleic acid bases), their metabolism in isolated cells and excretion in whole animals, as well as the many types of biological activities described so far, including cytotoxicity, genotoxicity, chemotactic, and effects on cell proliferation and gene expression. Structurally related compounds, such as acrolein, crotonaldehyde, and other 2-alkenals are also briefly discussed, since they have some properties in common with 4-hydroxyalkenals.
Recent studies demonstrate that cellular, molecular and morphological changes induced by stress in rats are accelerated when there is a pre-existing strain upon their already compromised adaptive responses to internal or external stimuli, such as may occur with uncontrolled diabetes mellitus. The deleterious actions of diabetes and stress may increase oxidative stress in the brain, leading to increases in neuronal vulnerability. In an attempt to determine if stress, diabetes or stress+diabetes increases oxidative stress in the hippocampus, radioimmunocytochemistry was performed using polyclonal antisera that recognize proteins conjugated by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). Radioimmunocytochemistry revealed that HNE protein conjugation is increased in all subregions of the hippocampus of streptozotocin (STZ) diabetic rats, rats subjected to restraint stress and STZ diabetic rats subjected to stress. Such increases were not significant in the cortex. Because increases in oxidative stress may contribute to stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization, we examined the stress/diabetes mediated HNE protein conjugation of the neuron specific glucose transporter, GLUT3. GLUT3 immunoprecipitated from hippocampal membranes of diabetic rats subjected to stress exhibited significant increases in HNE immunolabeling compared to control rats, suggesting that HNE protein conjugation of GLUT3 contributes to decreases in neuronal glucose utilization observed during diabetes and exposure to stress. Collectively, these results demonstrate that the hippocampus is vulnerable to increases in oxidative stress produced by diabetes and stress. In addition, increases in HNE protein conjugation of GLUT3 provide a potential mechanism for stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization.
We investigated the effect of psychological stress on lipid peroxidation activity in the mouse brain, the mechanism underlying the psychological stress-induced change in the activity, and the effects of anxiolytic and anxiogenic drugs on the activity in psychologically-stressed animals. Psychological stress exposure using a communication box paradigm for 2-16 h significantly increased the content of thiobarbituric acid reactive substance (TBARS), an index of lipid peroxidation activity, in the brain, and the effect was maximal after peaked by a 4-h stress exposure. In the animals stressed for over 4 h, the increased brain TBARS content lasted for 30 min after the stress exposure, while no significant increase of the TBARS content was observed in the liver or serum. Trolox (67.6 mg/kg, i.p.), an antioxidant drug, but not monoamine oxidase inhibitors, clorgyline (2.5-5 mg/kg, i.p.) or 5-(4-benzylphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-o ne (1-5 mg/kg, i.p.), significantly suppressed the effect of psychological stress. The non-selective nitric oxide (NO) synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10-100 mg/kg, i.p.) and the selective neuronal NOS inhibitor 7-nitroindazole (25 and 50 mg/kg, i.p.), but not the inducible NOS inhibitor aminoguanidine (1-100 mg/kg, i.p.), dose dependently suppressed the psychological stress-induced enhancement of lipid peroxidation in the brain. L-Arginine (300 mg/kg, i.p.), a substrate of NOS, antagonized the effect of L-NAME. Measurements of NO metabolites revealed a significant increase of NO production in the brains of stressed mice. The benzodiazepine (BZD) receptor agonist diazepam (0.05-0.5 mg/kg, i.p.), the 5-HT(1A) receptor agonists (+/-)-8-hydroxy-di-propylaminotetralin and buspirone (0.1-1 mg/kg, i. p.), but not the 5-HT(3) receptor agonist MDL72222, dose-dependently suppressed the psychological stress-induced enhancement of brain lipid peroxidation. In contrast, the administration of anxiogenic drugs, FG7142 (an inverse BZD agonist: 1-10 mg/kg, i.p.) and 1-(3-chlorophenyl)piperazine (a mixed 5-HT(2A/2B/2C) agonist: 0.1-1 mg/kg, i.p.), potentiated it. The effects of diazepam and FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a protective effect on oxidative brain membrane damage induced by psychological stress.
Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2'-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.
The aim of this study was to investigate the effect of chronic restraint stress (RS) on spatial learning and memory. Fifty healthy male Wistar rats, aged three months were used. They were equally divided into five groups--C: Control, W: Water Maze, CS-1: Restrained for 21 days (1 h/day) + water maze protocol following stress period, CS-2: Restrained for 28 days (1 h/day) + water maze protocol during last 7 days of stress period, CS-3: Restrained for 21 days and allowed to recovery for 7 days (1 h/day). Corticosterone levels were higher in all stress groups than in C and W groups. Nitrite levels of frontal cortex and hippocampus were found to be elevated in chronic stress groups with respect to C and W groups. Thiobarbituric acid reactive substances (TBARS) of both tissues were increased significantly in CS1 and CS2 groups compared with C, W, and CS3 groups. Escape latencies of CS1 and CS2 groups were longer than those of the W group on each day of acquisition. In transfer test, CS1 and CS2 groups stayed significantly shorter in target quadrant according to the W group. Significant correlations between corticosterone and either nitrite or TBARS of hippocampus and frontal cortex were found. Both acquisition and memory performances were negatively correlated with plasma corticosterone level, nitrite, and TBARS levels of hippocampus and frontal cortex. The results of this study suggest that stress-induced lipid peroxidation may affect the acquisition and memory performances.
Mice deficient in CuZn superoxide dismutase (CuZnSOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1-/- mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1-/- and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1-/- mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.
It has been shown that emotional stress may induce oxidative damage, and considerably change the balance between pro-oxidant and antioxidant factors in the brain. The aim of this study was to verify the effect of repeated restraint stress (RRS; 1 h/day during 40 days) on several parameters of oxidative stress in the hippocampus of adult Wistar rats. We evaluated the lipid peroxide levels (assessed by TBARS levels), the production of free radicals (evaluated by the DCF test), the total radical-trapping potential (TRAP) and the total antioxidant reactivity (TAR) levels, and antioxidant enzyme activities (SOD, GPx and CAT) in hippocampus of rats. The results showed that RRS induced an increase in TBARS levels and in GPx activity, while TAR was reduced. We concluded that RRS induces oxidative stress in the rat hippocampus, and that these alterations may contribute to the deleterious effects observed after prolonged stress.
Diet and exercise have a profound impact on brain function. In particular, natural nutrients found in plants may influence neuronal survival and plasticity. Here, we tested whether consumption of a plant-derived flavanol, (-)epicatechin, enhances cognition in sedentary or wheel-running female C57BL/6 mice. Retention of spatial memory in the water maze was enhanced by ingestion of (-)epicatechin, especially in combination with exercise. Improved spatial memory was associated with increased angiogenesis and neuronal spine density, but not newborn cell survival, in the dentate gyrus of the hippocampus. Moreover, microarray analysis showed upregulation of genes associated with learning and downregulation of markers of neurodegeneration in the hippocampus. Together, our data show that ingestion of a single flavanol improves spatial memory retention in adult mammals.
Retinol, alpha-tocopherol, lycopene, and alpha- and beta-carotene can be simultaneously determined in human plasma by reversed-phase liquid chromatography. Plasma--0.5 mL plus added internal standard, retinyl acetate--is deproteinized with 0.5 mL of ethanol, then extracted with 1.0 mL of petroleum ether. The organic layer is removed and evaporated, the residue is redissolved in 0.25 mL of ethanol, and 8-microL samples are injected into a 60 X 4.6 mm column of Hypersil ODS 3-microns particles at 35 degrees C. An isocratic methanol mobile phase, flow rate 0.9 mL/min, is used for the 9-min run. Retinol and retinyl acetate are monitored at 305 nm, the tocopherols at 292 nm, and the carotenoids at 460 nm. Between-run CVs were 3.1, 6.9, 6.1, and 6.5% for retinol, alpha-tocopherol, lycopene, and beta-carotene, respectively. Small sample requirement, simplicity of extraction, short run time, and good reproducibility make this procedure ideal for clinical or research use.
Developments of an open-field water-maze procedure in which rats learn to escape from opaque water onto a hidden platform are described. These include a procedure (A) for automatically tracking the spatial location of a hooded rat without the use of attached light-emitting diodes; (B) for studying different aspects of spatial memory (e.g. working memory); and (C) for studying non-spatial discrimination learning. The speed with which rats learn these tasks suggests that they may lend themselves to a variety of behavioural investigations, including pharmacological work and studies of cerebral function.
Myocardial deterioration is relentlessly progressive in almost all patients who develop overt symptoms. Many dilated cardiomyopathies are associated with a marked increase in cardiac sympathetic tone which may be toxic to myocytes. Microvascular spasm, leading to diffuse, focal reperfusion injury, also appears to be an important mechanism of cardiomyocyte loss in many models of dilated cardiomyopathy. Free radicals may mediate both catecholamine-induced damage and reperfusion injury. We hypothesized that myocardial antioxidant reserve may be significantly reduced in dilated cardiomyopathy and that alpha-tocopheryl acetate may be of benefit. The enzymes superoxide dismutase, catalase and glutathione peroxidase were measured in the myocardial tissue of control and cardiomyopathic hamsters in early (25-50 days) and late (275-320 days) stages of the cardiomyopathy. In another study, myocardial glutathione peroxidase activity and protein oxidation was measured in control and late stage cardiomyopathic hamsters receiving alpha-tocopheryl (70 mg/kg/day) or vehicle for 1 month. There were no significant differences in glutathione peroxidase activity between control and cardiomyopathic hamsters in the early stage of the cardiomyopathy. Superoxide dismutase and catalase activities did not change with aging; however, glutathione peroxidase decreased over 30%, alpha-tocopherol was reduced by approximately 50% and protein oxidation increased more than 2-fold in the hearts of late stage cardiomyopathic hamsters. Alpha-tocopheryl acetate administration restored alpha-tocopherol levels, glutathione peroxidase activity and protein oxidation to normal. We conclude that the decompensating heart has significantly limited antioxidant reserve and that this reserve is sensitive to the intake of antioxidant supplements.
The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory.
Physical exercise ameliorates age-related neuronal loss and is currently recommended as a therapeutical aid in several neurodegenerative diseases. However, evidence is still lacking to firmly establish whether exercise constitutes a practical neuroprotective strategy. We now show that exercise provides a remarkable protection against brain insults of different etiology and anatomy. Laboratory rodents were submitted to treadmill running (1 km/d) either before or after neurotoxin insult of the hippocampus (domoic acid) or the brainstem (3-acetylpyridine) or along progression of inherited neurodegeneration affecting the cerebellum (Purkinje cell degeneration). In all cases, animals show recovery of behavioral performance compared with sedentary ones, i.e., intact spatial memory in hippocampal-injured mice, and normal or near to normal motor coordination in brainstem- and cerebellum-damaged animals. Furthermore, exercise blocked neuronal impairment or loss in all types of injuries. Because circulating insulin-like growth factor I (IGF-I), a potent neurotrophic hormone, mediates many of the effects of exercise on the brain, we determined whether neuroprotection by exercise is mediated by IGF-I. Indeed, subcutaneous administration of a blocking anti-IGF-I antibody to exercising animals to inhibit exercise-induced brain uptake of IGF-I abrogates the protective effects of exercise in all types of lesions; antibody-treated animals showed sedentary-like brain damage. These results indicate that exercise prevents and protects from brain damage through increased uptake of circulating IGF-I by the brain. The practice of physical exercise is thus strongly recommended as a preventive measure against neuronal demise. These findings also support the use of IGF-I as a therapeutical aid in brain diseases coursing with either acute or progressive neuronal death.
The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.
The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.
The present study investigated whether infusion of brain-derived neurotrophic factor (BDNF) could ameliorate stress-induced impairments in spatial learning and memory as well as hippocampal long-term potentiation (LTP) of rats. Chronic immobilization stress (2 h/day x 7 days) significantly impaired spatial performance in the Morris water maze, elevated plasma corticosterone, and attenuated LTP in hippocampal slices from these animals as compared with normal control subjects. BDNF was infused into the left hippocampus (0.5 mul/h) for 14 days, beginning 7 days before the stress exposure. The BDNF group was protected from the deleterious effects of stress and performed at a level indistinguishable from normal control animals despite the presence of elevated corticosterone. BDNF alone and sham infusions had no effect on performance or LTP. These results demonstrate that spatial learning and memory, and LTP, a candidate neural substrate of learning and memory, are compromised during chronic stress, and may be protected by BDNF administration.
Previous studies have suggested that exercise in a running wheel can be neuroprotective, perhaps due to, among others, gene-expression changes after exercise, increases in trophic proteins and/or enhanced cardiovascular responsivity. Here we ask whether physical exercise or environmental enrichment provide protection after brain damage, especially in terms of recovery of cognitive function. To evaluate the neuroprotective effect of these conditions, we used the kainic acid (KA) model of neuronal injury. Systemically-administered KA induces excitotoxicity by overstimulation of glutamate receptors, resulting in neuronal death by necrosis and apoptosis. Our results show that exercise, but not enriched environment, prior to KA-induced brain damage, improved behavioural performance in both Morris watermaze and object exploration tasks. However, prior exercise did not decrease to control levels the hyperactivity normally seen in KA-treated animals, as measured by ambulation in the open field. Furthermore, both exercise and enriched environment did not protect against neuron loss in CA1, CA2 and CA3 areas of the hippocampus, despite a substantial increase in brain-derived neutrophic factor (BDNF) levels in dentate gyrus of the exercise and KA-treated animals.
The study deals with activity of three antioxidant enzymes, copper, zinc-superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), catalase (CAT) in hippocampus of rats, following the exposure to single chronic (individual housing or forced swimming) and acute (immobilization or cold) stress, as well as to combined chronic/acute stress. In addition, plasma noradrenaline (NA) and adrenaline (A) concentrations were measured in the same stress conditions, because their autooxidation can add to the oxidative stress. We observed that i) long-term social isolation and repeated forced swimming had minor effects on plasma catecholamines, but in the long-term pretreated groups, acute stressors caused profound elevation NA and A levels, ii) chronic stressors activate antioxidant enzymes, iii) acute stressors decrease catalase activity, their effects on CuZnSOD appear to be stressor-dependent, whereas MnSOD is not affected by acute stressors, and iv) pre-exposure to chronic stress affects the antioxidant-related effects of acute stressors, but this effect depends to a large extent on the type of the chronic stressor. Based on both metabolic and neuroendocrine data, long-term isolation appears to be a robust psychological stressor and to induce a "priming" effect specifically on the CuZnSOD and CAT activity.
Previous studies have shown that running exercise, either alone or in combination with antidepressant treatment, results in increased hippocampal BDNF levels. Nitric oxide (NO) is an important signaling molecule that has neuronal survival-promoting properties and has been shown to play an important role in plasticity associated with activating interventions. Herein, we administered the NO synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in conjunction with the monoamine oxidase inhibitor (MAOI) antidepressant, tranylcypromine, and voluntary wheel-running exercise to determine whether the enhancement in full-length BDNF mRNA occurring with these interventions is dependent upon NO synthesis. Our results demonstrate that both chronic exercise and chronic exercise-plus-tranylcypromine lead to enhanced hippocampal BDNF mRNA and protein expression. NOS inhibition prevents this effect of chronic exercise, but only partly prevents the effects of the exercise/antidepressant combination. Thus, the robust enhancement in BDNF mRNA occurring with exercise appears to be NO synthesis-dependent, but the intervention including antidepressant may enhance BDNF expression through alternative intracellular mechanisms. In addition, because exercise and antidepressants have both been shown to activate survival-promoting genes, we evaluated the levels of hippocampal phosphatidylinositol 3' kinase (PI-3K), an important signaling molecule within a principal neuronal survival-promoting intracellular pathway. Like BDNF mRNA and protein, exercise increases the expression of PI-3K, whereas concomitant NOS inhibition prevents this increase in PI-3K immunoreactivity above control levels. Our results are discussed in light of possible overlapping, but distinct intracellular pathways activated by exercise and antidepressant treatment to bring about enhancements in BDNF expression and other survival-promoting effects. These findings further demonstrate the potential therapeutic potential of chronic exercise to supplement pharmacotherapeutic treatment of mood disorders.
We describe a novel phenotype in mice lacking the major antioxidant enzyme, CuZn-superoxide dismutase (Sod1(-/-) mice), namely a dramatic acceleration of age-related loss of skeletal muscle mass. Sod1(-/-) mice are 17 to 20% smaller and have a significantly lower muscle mass than wild-type mice as early as 3 to 4 months of age. Muscle mass in the Sod1(-/-) mice is further reduced with age and by 20 months, the hind-limb muscle mass in Sod1(-/-) mice is nearly 50% lower than in age-matched wild-type mice. Skeletal muscle tissue from young Sod1(-/-) mice has elevated oxidative damage to proteins, lipids, and DNA compared to muscle from young wild-type mice. The reduction in muscle mass and elevated oxidative damage are accompanied by a 40% decrease in voluntary wheel running by 6 months of age and decreased performance on the Rota-rod test at 13 months of age, but are not associated with a decline in overall spontaneous activity. In some of the old Sod1(-/-) mice, the loss in muscle mass is also associated with the presence of tremors and gait disturbances. Thus, the absence of CuZnSOD imposes elevated oxidative stress, loss of muscle mass, and physiological consequences that resemble an acceleration of normal age-related sarcopenia.
Prevention of cardiovascular disease should target high-risk subjects based on genetic/familial factors, blood chemistry, blood pressure, body mass index (BMI), and a history of/or current cigarette smoking. We selected active adults (n=76) aged 30-60 and investigated these risk factors, in order to recommend preventive measures. Another interesting variable is the preclinical status or atheroma of the arterial (carotid) wall or lumen. We also investigated the presence of oxidative stress in, and the anti-oxidant status of these subjects. We studied the anti-oxidative efficacy of superoxide dismutase (SOD) and variations of malondialdehyde (MDA). Supplementation with GliSODin, a vegetal SOD associated with gliadin, was effective in controlling the thickness of the carotid artery intima and media layers as measured by ultrasonography-B. We could demonstrate the preventive efficacy of GliSODin at a preclinical stage in subjects with risk factors of cardiovascular disease.
Stress is thought to influence human eating behavior and has been examined in animal and human studies. Our understanding of the stress-eating relation is confounded by limitations inherent in the study designs; however, we can make some tentative conclusions that support the notion that stress can influence eating patterns in humans. Stress appears to alter overall food intake in two ways, resulting in under- or overeating, which may be influenced by stressor severity. Chronic life stress seems to be associated with a greater preference for energy- and nutrient-dense foods, namely those that are high in sugar and fat. Evidence from longitudinal studies suggests that chronic life stress may be causally linked to weight gain, with a greater effect seen in men. Stress-induced eating may be one factor contributing to the development of obesity. Future studies that measure biological markers of stress will assist our understanding of the physiologic mechanism underlying the stress-eating relation and how stress might be linked to neurotransmitters and hormones that control appetite.
Experiences during brain development may influence the pathogenesis of developmental disorders. Thus, social isolation (SI) rearing after weaning is a useful animal model for studying the pathological mechanisms of such psychiatric diseases. In this study, we examined the effect of SI on neurogenesis in the hippocampal dentate gyrus (DG) relating to memory and emotion-related behaviors. When newly divided cells were labeled with 5-bromo-2'-deoxyuridine (BrdU) before SI, the number of BrdU-positive cells and the rate of differentiation into neurons were significantly decreased after 4-week SI compared with those in group-housed mice. Repeated treatment of fluoxetine prevented the SI-induced impairment of survival of newly divided cells and ameliorated spatial memory impairment and part of aggression in SI mice. Furthermore, we investigated the changes in gene expression in the DG of SI mice by using DNA microarray and real-time PCR. We finally found that SI reduced the expression of development-related genes Nurr1 and Npas4. These findings suggest that communication in juvenile is important in the survival and differentiation of newly divided cells, which may be associated with memory and aggression, and raise the possibility that the reduced expression of Nurr1 and/or Npas4 may contribute to the impairment of neurogenesis and memory and aggression induced by SI.
Oxidative stress and modulation of anti-oxidant enzymes may contribute to the deleterious consequences of diabetes mellitus and to the effects of chronic (i.e. 21 day) stress in the CNS. We therefore compared the effects of short- and long-term exposure to diabetes-induced hyperglycemia, restraint stress and the combined effects of restraint stress and diabetes upon parameters of oxidative stress in the rat hippocampus. Whereas 7 days of restraint stress or hyperglycemia, or the combination, produced similar increases in oxidative stress markers 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) throughout the hippocampus, 21 days of stress or hyperglycemia did not increase these markers in the dentate gyrus. In contrast, Ammon's horn still showed elevated levels of these lipid peroxidation products, especially in diabetic rats subjected to 21 days of restraint stress. The expression of two anti-oxidant enzymes, copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD, was also differentially regulated by stress and hyperglycemia in a time- and region-specific manner in the rat hippocampus. Although long-term stress decreased both SOD isoforms, diabetes increased Cu/Zn-SOD expression in DG with or without 21 days of repeated stress. These increases may account for the finding that protein-conjugated HNE and MDA levels returned to control levels between 7 days and 21 days of hyperglycemia or the combination of diabetes and stress. These results suggest that while other anti-oxidant pathways may account for decreases in oxidative stress in the long-term stress paradigm, increases in Cu/Zn-SOD expression may contribute to the region-specific attenuation of oxidative stress in the diabetic rat hippocampus.
Relationshipbetweenstress,eatingbehavior,andobesity
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TorresSJ,NowsonCA.Relationshipbetweenstress,eatingbehavior,andobesity. Nutrition 2007;23:887–94.