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The change of circulating insulin like growth factor binding protein 7 levels may correlate with postoperative cognitive dysfunction
Abstract
Insulin-like growth factor binding protein (IGFBP) 7 may be a critical regulator of memory consolidation. This study was performed to assess the relationship between circulating IGFBP7 levels and postoperative cognition dysfunction (POCD) in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. Among one hundred and two patients included in this study, forty-four patients completed collection of all four blood samples and thirty-five patients were diagnosed with POCD. The results of Mini-Mental State Examination (MMSE) test and enzyme-linked immunosorbent assay showed that postoperative MMSE score and circulating insulin-like growth factor (IGF)-1 level were lower and circulating IGFBP7 level was higher than preoperative level. Circulating IGF-1 level was significantly lower and D-value of preoperative and postoperative day 1 circulating IGFBP7 levels (ΔIGFBP7(1)) was significantly higher in the POCD group. Age preoperative MMSE, IGF-1 level and ΔIGFBP7(1) significantly correlated with POCD, but preoperative IGFBP7 level not. Logistic regression analysis revealed that older patients, lower preoperative MMSE score, IGF-1 level and higher IGFBP7 level significantly increased the risk of POCD, but ΔIGFBP7(1) not. Hence, circulating IGF-1 and IGFBP7 levels and their changes during operation under general anesthesia may correlate with POCD, but further investigation in larger samples is needed.
Copyright © 2014. Published by Elsevier Ireland Ltd.
... In contrast to IGFBP1 to IGFBP6, which bind to the IGFs (Firth and Baxter 2002), IGFBP7 is a critical regulator of memory consolidation that can attenuate the function of ILPs (Agbemenyah et al. 2013) and can directly bind to the IGF-1R and thereby inhibit its activity (Evdokimova et al. 2012). The relationship between circulating IGFBP7 level and POCD had been discussed in previous work (Jiang et al. 2015). ...
... The study was performed in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. The data can be seen in our previous work (Jiang et al. 2015). All patients underwent a standardized clinical evaluation that included medical history and cognitive function assessment (mini-mental state examination; MMSE) (Rosario 2010). ...
... The details of procedure of anesthesia and surgery can be seen in our previous work (Jiang et al. 2015). ...
Insulin-like growth factor (IGF)-1 is implicated in learning and memory. Experimental studies have suggested that the IGF-1 system is beneficial in cognition, especially in Alzheimer's disease (AD), by opposing Aβ amyloid processing and hyperphosphorylated tau toxicity. Low IGF-I and insulin-like growth factor binding protein (IGFBP)-3 serum levels are significantly associated with AD. To assess the relationship between circulating IGF-I and IGFBP3 levels and change of postoperative cognition. The study was performed in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. On the day before the operation and postoperative days 1, 3 and 7, mini-mental state examination (MMSE) was performed by the same doctor, and blood samples were collected at 08:00 h after overnight fasting. The circulating levels of IGF-1 and IGFBP3 were measured by enzyme-linked immunosorbent assay. One hundred and two patients completed all four MMSE tests and forty-four of them completed all the four blood samples collection. Postoperative circulating IGF-1 level, ratio of IGF-1/IGFBP3 and MMSE score significantly decreased, whereas IGFBP3 level significantly increased compared with preoperative values in total patients. The change trends of circulating IGF-1 level and MMSE score were similar. Preoperative circulating IGF-1 level, ratio and MMSE score were significantly lower in POCD group compared to non-POCD group. There was no significant difference in preoperative level of circulating IGFBP3 between the two groups. Preoperative circulating IGF-1 level was negatively correlated with age and positively with MMSE. Logistic regression analysis revealed that lower preoperative IGF-1 level and elderly patients increased the odds of POCD. Down-regulation of circulating IGF-1 level may be involved in the mechanism of postoperative cognitive dysfunction. Older patients had lower circulating IGF-1 levels and were more susceptible to POCD.
... Insulin-like growth factor binding protein 7 (IGFBP7) is a member of the IGF binding protein family, and is able to regulate cell proliferation, differentiation, angiogenesis, cell adhesion and cellular senescence in a variety of cells (18)(19)(20)(21)(22)(23). Furthermore, silence of IGFBP7 is associated with poor post-operative survival in various types of cancer, such as glioma, liver and colorectal cancer (24)(25)(26)(27). ...
... Cell treatment. Podocytes (3x10 5 cells/ml) were seeded in 6-wells plates, and treated with PBS and glucose at 5,10,20,40,60,80 or 100 mM at room temperature. The podocytes were then transferred to the incubator and held for 6, 12, 24 and 48 h at 37˚C. ...
Insulin-like growth factor-binding protein 7 (IGFBP7) has been identified as a secreted protein associated with a number of cellular processes. However, the specific regulatory mechanisms of IGFBP7 on podocytes of diabetic nephropathy (DN) are yet to be elucidated. In the present study, podocytes were identified initially via an immunofluorescence assay using an anti-synaptopodin antibody. It was subsequently demonstrated that glucose promoted podocyte proliferation in a time- and dose-dependent manner via MTT assay. In addition, IGFBP7 expression was silenced in podocytes via siRNA, the effects of which were evaluated using western blotting and reverse transcription-quantitative polymerase chain reaction. It was demonstrated that silencing IGFBP7 inhibited apoptosis and epithelial mesenchymal transformation (EMT) of podocytes mediated by high glucose (HG). Transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad) signaling was associated with proliferation, apoptotic activities and EMT. Therefore, the expression levels of TGF-β1/Smad pathway were detected, and it was observed that silencing IGFBP7 suppressed the TGF-β1/Smad pathway in podocytes induced by HG. These findings suggested that IGFBP7 may serve as a potential therapeutic target for DN.
... Circulating IGF-1 may traverse the blood-brain barrier (4) to increase Aβ clearance from the brain and reduce tau phosphorylation via inhibiting glycogen synthase kinase 3β (GSK3β) (5)(6)(7). Previous population-based studies involving elderly individuals have revealed that low circulating IGF-1 levels contribute to cognitive decline (8,9). A previous study demonstrated that circulating IGF-1 levels were reduced in patients anesthetized with sevoflurane, which negatively correlated with POCD (10). ...
... IGF-1 has been demonstrated to protect neurons against the toxic effects of Aβ (3) and reduce tau phosphorylation by inhibiting GSK3β (5,6). In addition, low concentrations of circulating IGF-1 may contribute to cognitive decline (8,9). This suggests that sevoflurane may 3'-untranslated region (UTR) of IGF-1. ...
Insulin-like growth factor (IGF)-1 functions as a neuroprotective hormone and may protect against cognitive impairment, which may occur as a result of sevoflurane exposure. The aim of the present study was to assess the effect of sevoflurane on the production of IGF‑1 and investigate the molecular mechanisms underlying this regulation. The BRL rat hepatocyte cell line and adult mice were exposed to 1 or 2 minimal alveolar concentrations sevoflurane for 4 or 8 h. IGF‑1 and microRNA‑98 levels were quantified using an enzyme‑linked immunosorbent assay, western blotting and reverse transcription‑quantitative polymerase chain reaction analyses. The importance of microRNA‑98 in the regulation of IGF‑1 by sevoflurane was investigated using a microRNA‑98 inhibitor. Sevoflurane treatment reduced IGF‑1 levels and simultaneously upregulated microRNA‑98 expression levelsin rat hepatocytes and adult mice. Inhibition of microRNA‑98 attenuated this effect. Therefore, sevoflurane may reduce the synthesis of IGF‑1 by upregulating microRNA‑98 expression.
... These proteins may interact with the cytoskeleton, 11,12 postsynaptic density protein 95 (PSD-95), cypin, and prion protein (PrP C ), which together organize cytoskeleton structure. [13][14][15] This review discusses the role of the cytoskeleton in allostasis in response to redox stress and cellular stress, 15,16 which results in neuroinflammation 17 and protein interactions of the axonal and synaptic densities. 18 PBM has been shown to have a direct effect on the cytoskeleton, which is directly involved in neural blockade, in pain modulation 19 and most probably in the preconditioning effects of PBM, which may also be important in preconditioning against POCD. ...
... 103 Recent studies have also shown some link between POCD in patients and levels of insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 7, both were believed to be important in memory consolidation and AD. 17 IL-6 has been suggested as playing a crucial role in the neuroinflammatory response leading to POCD. 130 Inflammatory cytokines have also been associated with POCD after cardiac surgery 131 and levels of S-100, an indicator of traumatic brain injury, was found to be an indicator of POCD. ...
Postoperative cognitive dysfunction (POCD) is a decline in memory following anaesthesia and surgery in elderly patients. While often reversible, it consumes medical resources, compromises patient well-being, and possibly accelerates progression into Alzheimer's disease. Anesthetics have been implicated in POCD, as has neuroinflammation, as indicated by cytokine inflammatory markers. Photobiomodulation (PBM) is an effective treatment for a number of conditions, including inflammation. PBM also has a direct effect on microtubule disassembly in neurons with the formation of small, reversible varicosities, which cause neural blockade and alleviation of pain symptoms. This mimics endogenously formed varicosities that are neuroprotective against damage, toxins, and the formation of larger, destructive varicosities and focal swellings. It is proposed that PBM may be effective as a preconditioning treatment against POCD; similar to the PBM treatment, protective and abscopal effects that have been demonstrated in experimental models of macular degeneration, neurological, and cardiac conditions.
... In the present study, the 30.56% incidence of POCD on the third day after non-cardiac surgery was lower than in comparable studies (Li et al., 2012;Jiang et al., 2015). Many of the findings in this field vary significantly from study to study, depending on different populations, assessment criteria, intervening measures, surgery types, and other factors. ...
In our previous experiment, we found that there were abnormal levels of circRNA-089763 in the plasma exosomes of patients with postoperative cognitive dysfunction (POCD) after cardiac surgery. Therefore, the aim of this study was to further investigate the relationship between plasma circRNA-089763 level and POCD in elderly patients after non-cardiac surgery. A prospective cohort study was conducted to select elderly patients undergoing elective non-cardiac surgery. A total of 72 patients were enrolled in this study, and cognitive functions were assessed 1 day before and 3 days after surgery by a series of neuropsychological measurements. Next, patients were divided into POCD and non-POCD (NPOCD) groups according to the Z score method. Blood was collected the day before and 3 days after surgery, and the plasma circRNA-089763 level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the difference and correlation in plasma circRNA-089763 levels between the POCD and NPOCD groups were analyzed. On the third day after surgery, the incidence of POCD was 30.56%. The relative level of circRNA-089763 in the POCD group was 2.41 times higher than that in the NPOCD group (t = 4.711, p < 0.001), patients in POCD group had higher age (t = 5.971, p < 0.001), higher American Society of Anesthesiologists classification (χ2 = 14.726, p < 0.001), less years of education (t = 2.449, p = 0.017), more intraoperative blood loss (t = 3.196, p = 0.002), and higher visual analog scale (VAS) scores (t = 10.45, p < 0.001). The binary logistic regression analysis showed that the circRNA-089763 level, age, and intraoperative blood loss were independently associated with POCD (OR: 2.75, 95% CI: 1.261–5.999, p = 0.011; OR: 1.32, 95% CI: 1.114–1.565, p = 0.001; OR: 1.017, 95% CI: 1.004–1.03, p = 0.011). These results demonstrated that the circRNA-089763 plasma level was related to POCD after non-cardiac surgery in elderly patients.
... IGFBP-7 plays an important controlling role in memory consolidation [32]. Changes in IGFBP-7 levels have been correlated with postoperative cognitive dysfunction and AD-like memory impairments [27,45]. Our present study demonstrated that the levels of both serum IGFBP-3 and IGFBP-7 were markedly reduced in schizophrenia patients, while there was no significant association between either IGFBP-3 or IGFBP-7 levels and the psychotic and cognitive symptoms in the patients. ...
Background
Schizophrenia is linked with abnormal brain neurodevelopment, on which IGF-2 (insulin-like growth factor-2) has a great impact. The purpose of this study was to assess the levels of serum IGF-2 and its binding proteins IGFBP-3 and IGFBP-7 in schizophrenia patients and the associations of these proteins with schizophrenia psychopathology and cognitive deficits.
Methods
Thirty-two schizophrenia patients and 30 healthy controls were recruited. The PANSS and a neurocognitive test battery were used to assess schizophrenic symptomatology and cognition, respectively. Serum IGF-2, IGFBP-3 and IGFBP-7 levels were determined using ELISA.
Results
The schizophrenia patients had a much lower content of serum IGF-2, IGFBP-3 and IGFBP-7 than controls. For the patients, IGF-2 levels were negatively correlated with the PANSS negative scores and positively associated with working memory, attention, and executive function. The correlations between IGF-2 and the PANSS negative scores, working memory or executive function were still significant after controlling for age, sex, education level, BMI, illness history and age of onset. No significant associations of IGFBP-3 or IGFBP-7 with the PANSS scores and cognitive function were observed in the patients.
Conclusions
Our study demonstrates that serum IGF-2 was significantly correlated with negative and cognitive symptoms in patients with schizophrenia, suggesting that altered IGF-2 signaling may be implicated in the psychopathology and cognitive deficits in schizophrenia.
... Study staff were blinded to whether the patients had POCD in completing the postoperative questionnaires. According to MMSE score and the DMMSE >2, the patient was considered to have developed POCD [10]. In our study, 142 elderly patients were divided into a POCD group and a non-POCD group according to MMSE score, and ABO blood types were analyzed. ...
Background
Postoperative cognitive dysfunction (POCD) is a postoperative complication after surgery and anesthesia. Whether ABO blood types are associated with POCD in elderly patients undergoing unilateral total hip arthroplasty surgery in China is unclear.
Material/Methods
Firstly, 142 elderly patients were divided into a POCD group and a non-POCD group according to the Mini Mental State Examination (MMSE) scores and ABO blood types were analyzed. Secondly, according to ABO blood type, the selected 226 patients were divided into 4 groups: type A group, type B group, type AB group, and type O group. Then, all patients completed the MMSE before and after surgery. Finally, the occurrence of POCD was recorded and related data were analyzed.
Results
Firstly, there was a significant difference in both groups in terms of distribution of ABO blood types, and elderly patients who developed POCD were more likely to have type A blood and less likely to have type O blood. Secondly, compared with elderly patients with type A blood, those with type O had higher MMSE scores on the first day and the seventh day after surgery. Finally, the risk of developing POCD was significantly higher in patients with type A blood and on the first day and the seventh day after surgery the risk of developing POCD was significantly lower in patients with type O blood.
Conclusions
Elderly patients with type A blood have higher risk of developing early POCD and those with type O blood have less risk of developing early POCD.
Signaling pathways of tumor necrosis factor-α (TNF-α) and insulin-like growth factor-I (IGF-I) are found to be functionally interrelated in some experimental studies. IGF-I may be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). In order to investigate the possible interaction of TNF-α and IGF-I in POCD, the plasma levels of IGF-I and TNF-α were determined in 44 patients under general anesthesia. As compared with non-POCD patients, POCD patients showed increased TNF-α and decreased IGF-I levels in plasma, as well as a significant negative correlation between TNF-α and IGF-I values. The present results suggest that interaction of increased TNF-α levels and decreased IGF-1 levels might lead to a vicious circle, which may contribute to POCD.
Insulin-like growth factor 1 (IGF-1) is a neuroprotective hormone and a decrease in levels of circulating IGF-1 contributes toward cognitive decline. The aim of this study was to investigate the effect of sevoflurane on the level of circulating IGF-1 and cognitive function in aged mice and the role of circulating IGF-1 in the cognitive dysfunction induced by sevoflurane. Aged mice were exposed to 1 or 2 minimal alveolar concentrations of sevoflurane for 4 or 8 h. Before and after the exposure, blood was collected from the tail vein and serum IGF-1 was measured by an enzyme-linked immunosorbent assay. After exposure, spatial learning and memory were tested in the Morris water maze. An intraperitoneal injection of IGF-1 was used to study the role of IGF-1 in the cognitive impairment induced by sevoflurane. Sevoflurane dose dependently decreased the serum IGF-1 concentration, and resulted in aged mice taking significantly longer and traveling significantly further to find the platform. Sevoflurane significantly decreased the times crossing the platform and %time spent in target quadrant relative to the control group. IGF-1 attenuated this effect, but could not completely reverse it. We conclude that downregulation of circulating IGF-1 contributes toward the cognitive impairment induced by sevoflurane.
Severe insulin resistance(IR) promotes the development of Alzheimer disease. IR and postoperative cognitive dysfunction (POCD) are a common complication during the cardiac perioperative period. The authors hypothesized that IR of individuals with cardiac valve surgery would have increased the risk of POCD. The purpose of the study was to analyze the association of IR and POCD after cardiac valve surgery. Total 131 patients who underwent valve replacement via cardiopulmonary bypass(CPB) were included. Cognitive function was assessed by a series of neuropsychological measurements at 1 day before and 7 days after the surgery. 40 healthy volunteers as the control group also completed the neuropsychological assessment at the same time point. POCD was identified using the “Z score” method. Fasting blood glucose and insulin levels were detected before anesthesia and at 6 hours and 7 days post-operation. Additionally serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) were measured at 6 hours post-operation. The insulin resistance index was calculated by “homeostasis model assessment 2” (HOMA2) software. The relationship between IR and POCD or TNF-α、IL-6 was then analyzed. At 7 days after surgery, the incidence of POCD was 43.8%. The levels of HOMA2-IR in patients with POCD were significantly higher than those of patients without POCD at 6 hours and 7 days after operation (P<0.05).The levels of serum IL-6 and TNF- α were positively correlated with HOMA2-IR value at 6 hours after operation (RIL-6=0.426, P<0.01; RTNF-a=0.381, P<0.01). POCD was correlated with the patients’ education age (OR=1.062), CPB time (OR=1.018), self-rating depression scale(SDS) score after operation(OR=1.082), HOMA2-IR at 6 hours(OR=1.110) and 7 days (OR=13.762) after operation, IL-6 (OR=1.036) and TNF-α (OR=1.039) at 6h after operation. Our study suggests that IR is correlated with the incidence of POCD and the increase of inflammatory factors.
Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer's disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-β (Aβ) biogenesis is unclear. In this study using female AβPPsw/PS1ΔE9 mice, we found that the level of Aβ40 was fairly constant in 6- to 15-month-old brains, whereas Aβ42 was only significantly increased in the 15-month-old brain. In contrast, increased levels of IRβ, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AβPPsw/PS1ΔE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aβ42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AβPPsw/PS1ΔE9 mouse brain. Furthermore, the expression profile of IRβ, IRS-2, and p85/PI3K in AβPPsw/PS1ΔE9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in AβPPsw/PS1ΔE9 mice.
Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.
To determine the normal values of serum IGF-1 (Immulite 2000) in a Brazilian adult (21-70 years) population.
Healthy volunteers were divided into 10 groups according to age (5-year intervals), with 100 subjects (50 men and 50 women) per group. One-hundred participants were selected for repetition of the test after 12 weeks.
No difference in IGF-1 values was observed between men and women, but a progressive reduction of serum IGF-1 with age was seen. The reference values provided by the manufacturer of the assay, although discretely higher, were very close to the values found in this study. A second measurement of IGF-1 after 12 weeks revealed a variation < 20% in 99% of subjects.
This study established the reference range for IGF-1 determined with the Immulite 2000 assay for a large number of healthy Brazilian adults stratified according to age, and suggests that variations > 20% in IGF-1 levels within an interval of 12 weeks cannot be attributed to interassay variability.
To investigate the effects of sevoflurane on cognitive function in old Sprague-Dawley (SD) rats and the expression of insulin-like growth factor-1 (IGF-1) in CA1 region of hippocampus. Forty Sprague-Dawley rats of 12 months old were randomly divided into five groups: the normal control group; 1.5% sevoflurane I group (be tested after received 1.5% sevoflurane for 1 day); 1.5% sevoflurane II group (be tested after received 1.5% sevoflurane for 7 day); 3.0% sevoflurane I group (be tested after received 3.0% sevoflurane for 1 day) and 3.0% sevoflurane II group (be tested after received 3.0% sevoflurane for 7 day). All SD rats were received 1.5 or 3.0% sevoflurane in a special glass anesthesia box for 2 h respectively, except for the normal control group. Y-maze was used to test the ability of learning and memory after being received sevoflurane for 1 or 7 days at the same moment portion. The altered expression level of IGF-1 in the hippocampus was tested to compare its transcripts by RT-PCR analysis. The results showed that 3% sevoflurane induced the decline of cognitive function and significantly deceased the IGF-1 expression at mRNA levels at 1 day in the 3.0% sevoflurane I group when compared with the normal control group. However, there were no significant difference among the other groups when compared with normal control group. Therefore, administration of sevoflurane might temporally affect the ability of cognitive function of rats through suppressing the IGF-1 expression at mRNA levels in hippocampus.
Insulin and insulin-like growth factors I and II (IGF-I and IGF-II) have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action in the brain are unknown. Since central neurons are particularly vulnerable to hypoglycemia that results from ischemia or other insults, we tested the hypothesis that growth factors can protect central neurons against hypoglycemic damage in vitro. IGF-I and IGF-II (3-100 ng/ml) each prevented glucose deprivation-induced neuronal damage in a dose-dependent manner in rat hippocampal and septal cell cultures. High concentrations of insulin (greater than 1 microgram/ml) also protected neurons against hypoglycemic damage. Epidermal growth factor did not protect against hypoglycemic damage. Both IGFs and insulin were effective when administered 24 hr before or immediately following the onset of glucose deprivation. Direct measurements of intraneuronal calcium levels and manipulations of calcium influx demonstrated that calcium influx and sustained elevations in intraneuronal calcium levels mediated the hypoglycemic damage. IGF-I and IGF-II each prevented the hypoglycemia-induced elevations of intraneuronal free calcium. Studies with excitatory amino acid receptor antagonists and calcium channel blockers indicated that NMDA receptors did, and L-type calcium channels did not, play a major role in hypoglycemic damage. Taken together, these findings indicate that IGFs can stabilize neuronal calcium homeostasis and thereby protect against hypoglycemic damage.
Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary lesions associated with Alzheimer's disease. Hyperphosphorylation reduces the affinity of tau for microtubules and is thought to be a critical event in the pathogenesis of this disease. Recently, glycogen-synthase kinase-3 has been shown to phosphorylate tau in vitro and in non-neuronal cells transfected with tau. The activity of glycogen-synthase kinase-3 can be down-regulated in response to insulin or insulin-like growth factor-1 through the activation of the phosphatidylinositol 3-kinase pathway. We therefore hypothesize that insulin or insulin-like growth factor-1 may affect tau phosphorylation through the inhibition of glycogen-synthase kinase-3 in neurons. Using cultured human neuronal NT2N cells, we demonstrate that glycogen-synthase kinase-3 phosphorylates tau and reduces its affinity for microtubules and that insulin and insulin-like growth factor-1 stimulation reduces tau phosphorylation and promotes tau binding to microtubules. We further demonstrate that these effects of insulin and insulin-like growth factor-1 are mediated through the inhibition of glycogen-synthase kinase-3 via the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.
Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Abeta levels are found at an early age in mutant mice with low circulating IGF-I, and Abeta burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain Abeta levels reflects the ability of IGF-I to induce clearance of brain Abeta, probably by enhancing transport of Abeta carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-alpha, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain Abeta burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.
The possibility that perturbed insulin/insulin-like growth factor I (IGF-I) signalling is involved in development of late-onset forms of Alzheimer's disease (AD) is gaining increasing attention. We recently reported that circulating IGF-I participates in brain amyloid beta (Abeta) clearance by modulating choroid plexus function. We now present evidence that blockade of the IGF-I receptor in the choroid plexus originates changes in brain that are reminiscent of those found in AD. In rodents, IGF-I receptor impairment led to brain amyloidosis, cognitive disturbance, and hyperphosphorylated tau deposits together with other changes found in Alzheimer's disease such as gliosis and synaptic protein loss. While these disturbances were mostly corrected by restoring receptor function, blockade of the IGF-I receptor exacerbated AD-like pathology in old mutant mice already affected of brain amyloidosis and cognitive derangement. These findings may provide new cues into the causes of late-onset Alzheimer's disease in humans giving credence to the notion that an abnormal age-associated decline in IGF-I input to the choroid plexus may contribute to development of AD in genetically prone subjects.
Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative disorders. Toxic protein aggregates have been identified as potential contributory factors, including amyloid beta-protein in Alzheimer's disease, tau in frontotemporal dementia, and alpha-synuclein in Parkinson's disease. However, current models of pathogenesis do not explain the origin of the common sporadic forms of these diseases or address the critical nexus between aging and disease. This review discusses potential approaches to unifying the systems biology of the aging brain with the pathogenesis of neurodegeneration.
Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Abeta levels are found at an early age in mutant mice with low circulating IGF-I, and Abeta burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain Abeta levels reflects the ability of IGF-I to induce clearance of brain Abeta, probably by enhancing transport of Abeta carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-alpha, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain Abeta burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.
Insulin-like growth factors (IGF) 1 and 2 are known as potential mitogens for normal and neoplastic cells. IGF2 is a main fetal growth factor while IGF1 is activated through growth hormone action during postnatal growth and development. However, there is strong evidence that activation of IGF2 by its E2F transcription factor 3 (E2F3) is present in different types of cancer. Also high levels of IGF1 strongly correlate with cancer development due to anti-apoptotic properties and enhancement of cancer cell differentiation, which can be attenuated by IGFBP3. Head and neck cancer is known as one of the six most common human cancers. The main risk factor for head and neck cancer is consumption of tobacco and alcohol as well as viral infection and bacterial infection by stimulation of chronic local inflammation. There is also a genetic basis for this form of cancer; however, the genetic markers are not yet established. In this study we investigated the levels of the expression of IGF2, IGF1, E2F3 and IGFBP3 in human cancers and healthy tissues surrounding the tumor obtained from each of 41 patients. Our study indicated that there is no alteration of the levels of expression of IGF2, E2F3 and IGF1 in head and neck squamous cell carcinoma (HNSCC) cases studied in selected experimental population, but there was evidence for upregulation of pro-apoptotic IGFBP3 in cancer when comparing to healthy tissue. These important findings indicate that insulin-growth factors are not directly associated with HNSCC showing some variability between patients and location of tumor. However, elevated level of IGFBP3 suggests possible regulatory role of IGF signal by its binding protein in this type of tumor.
Anliegen: Mit der Studie wird die Inzidenz postoperativer Delirien bestimmt. Um Hinweise auf Präventionsmöglichkeiten zu erhalten, wird die Assoziation zwischen Inzidenz und Risikofaktoren geprüft. Methode: 200 konsekutive Patienten über 60 Jahre wurden prospektiv mit einem standardisierten Untersuchungsinstrumentarium präoperativ und täglich postoperativ untersucht. Die Assoziation zwischen Risikofaktoren und Delir wurde mittels multipler logistischer Regression analysiert. Ergebnisse: Bei 20,5 % der untersuchten Patienten trat postoperativ ein Delir auf. Bedeutsamste Risikofaktoren waren höheres Alter, geringere präoperative kognitive Leistung und somatische Komorbidität. Schlussfolgerungen: Die Resultate bestätigen eine hohe Delirinzidenz bei älteren Patienten. Es konnten nur wenige Hinweise auf modifizierbare Risikofaktoren gefunden werden.
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
McLAY, R.N., S.M. FREEMAN, R.E. HARLAN, C.F. IDE, A.J. KASTIN AND J.E. ZADINA Aging in the hippocampus: interrelated actions of neurotrophins and glucocorticoids. NEUROSCI BIOBEHAV REV 21(5) 615–629, 1997.—Over the past two decades, evidence has been accumulating that diffusible molecules, such as growth factors and steroid hormones, play an important part in neural senescence, particularly in the hippocampus. There is also evidence that these molecules do not act as independent signals, but show interrelated regulation and cooperative control over the aging process. Here, we review some of the changes that occur in the hippocampus with age, and the influence of two classes of signaling substances: glucocorticoids and neurotrophins. We also examine the interactions between these substances and how this could influence the aging process. Published by Elsevier Science Ltd.
Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, has been used to treat gynecological disorders and neural dysfunctions.
The present study was carried out to investigate the effects of DSS on cognitive ability and oxidative stress-related neuronal apoptosis in the hippocampus of aging mice induced by d-galactose (d-gal) to elucidate the underlying molecular mechanisms.
Ethanol extract of DSS (DE) were orally administered to d-gal-induced senescent mice for six weeks. The cognitive ability was determined by the methods of step-down type passive avoidance test and Morris water maze test. The activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS), and levels of carbonyl protein (CP), glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) were also examined. Furthermore, the expression of apoptotic related proteins in hippocampus of d-gal-treated mice, such as Bcl-2, Bax and caspase-3 proteins, were determined by immunohistochemistry.
DE at the doses of 1.8, 3.6 and 7.2g/kg significantly enhanced the cognitive performances and restored the abnormal activities of SOD and NOS and levels of CP, MDA, GSH and NO induced by d-gal. Moreover, the neural apoptosis in the hippocampus of d-gal-treated mice was improved by DE through regulating the expression of Bcl-2, Bax and caspase-3.
These results demonstrate that DE has neuroprotective effects in d-gal-induced senescent mice by ameliorating oxidative stress induced neuronal apoptosis in the brain.
There is a growing interest in the involvement of anesthetic agents in the etiology of postoperative cognitive dysfunction. Recent animal studies suggest that acute anesthesia induces transient hyperphosphorylation of tau, an effect essentially ascribed to hypothermia. The main aim of the present study was to investigate effects, in normothermic conditions, of acute or repeated exposure to sevoflurane, a halogenated anesthetic agent, on hippocampal tau phosphorylation and spatial memory in adult mice.
5 to 6-month-old C57Bl6/J mice were submitted to acute (1 h) or repeated (five exposures of 1h every month) anesthesia using 1.5 or 2.5% sevoflurane, in normothermic conditions. In the acute protocol, animals were sacrificed 1 and 24 h after exposure. In the chronic protocol, spatial memory was evaluated using the Morris water maze following the fourth exposure, and tau phosphorylation evaluated 1 month following the last exposure using bi- and mono-dimensional electrophoresis.
Acute sevoflurane anesthesia in normothermic conditions led to a significant dose-dependent and reversible hippocampal tau phosphorylation, 1 h following the end of exposure (P < 0.001). Conversely, repeated anesthesia led to persistent tau hyperphosphorylation and significant memory impairments, as seen in the retention phase of the Morris water maze in sevoflurane-anesthesized animals. These pathologic features may be related to the activation of both Akt and Erk pathways.
The present study demonstrates, in mice, that sevoflurane exposure is associated with increased tau phosphorylation through specific kinases activation and spatial memory deficits. These data support a correlation between exposures to this anesthetic agent and cognitive decline.
The signalling pathways utilised by insulin receptor (IR) and IGF receptor to transduce their diverse effects on cellular metabolism, growth and survival are well established in broad outline, but many details remain to be elucidated. Tyrosine phosphorylation of IR substrates and Shc initiates signalling via canonical phosphoinositide 3-kinase/Akt and Ras/MAP kinase pathways, which together mediate many of the actions of insulin and IGFs. However, a variety of additional substrates and scaffolds have been described that may play roles in modulating the canonical pathways or in specific biological responses. This review will focus on recent studies that have extended our understanding of insulin/IGF signalling pathways, and the elements that may contribute to specificity.
Amyloid peptide (Aβ) is generated by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (Bace1) and γ-secretase. Aβ production increases after plasma membrane cholesterol loading through unknown mechanisms. To determine how APP-Bace1 proximity affects this phenomenon, we developed a fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET) technique for visualization of these molecules either by epifluorescence or at the plasma membrane only using total internal reflection fluorescence. Further, we used fluorescence correlation spectroscopy to determine the lipid rafts partition of APP-yellow fluorescent protein (YFP) and Bace1-green fluorescent protein (GFP) molecules at the plasma membrane of neurons. We show that less than 10 min after cholesterol exposure, Bace1-GFP/APP-mCherry proximity increases selectively at the membrane and APP relocalizes to raft domains, preceded by rapid endocytosis. After longer cholesterol exposures, APP and Bace1 are found in proximity intracellularly. We demonstrate that cholesterol loading does not increase Aβ production by having a direct impact on Bace1 catalytic activity but rather by altering the accessibility of Bace1 to its substrate, APP. This change in accessibility is mediated by clustering in lipid rafts, followed by rapid endocytosis.
Light changes in mental function after operation occur in patients of all ages, but more frequent they are observed in older patients. The incidence of early postoperative cognitive dysfunction varies depending on surgical procedure and may be as high as 20-90% in aged patients, and occurs most often in patients undergoing cardiovascular surgery. Early postoperative cognitive dysfunction is a predictor of late postoperative cognitive dysfunction. Delirium develops in at least 50% of older surgical patients and even more frequently after cardiac surgeries (72%). Postoperative delirium, like delirium manifesting with co-existing disease, and late postoperative cognitive dysfunction are strong predictors of functional and cognitive decline in one-year period after discharge and are associated with higher morbidity and mortality, longer hospital stay, and a higher rate of institutionalization. The reasons of postoperative cognitive dysfunction and delirium are not well understood. An assessment of cognitive function should be completed as a routine in older patients, and effective prevention requires the identification of risk factors for delirium: advanced age, preexisting dementia and depression, visual and hearing impairment, Parkinson disease, emergency operation, anticholinergic drugs, and others. After operation, elderly patients must be carefully monitored for probable postoperative delirium. It is important to deepen health care professionals' knowledge of postoperative cognitive complications in older surgical patients.
Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.
Ten male volunteers performed 3 tasks before, during, and following administration of 3 levels of alveolar halothane (0.05, 0.1, and 0.2%) for one-half hour each and (on a separate occasion) enflurane (0.15, 0.3, and 0.4%) for one-half hour each. The concentrations of halothane tested representing 7, 13, and 27% of MAC values, respectively; those of enflurane were 9, 18, and 24% of MAC. The tasks were a choice-reaction time test, a digit span test, and a Purdue Pegboard Assembly test. Volunteers also were tested for amnesia with word pairs and a picture. No effects or only slight effects on mental function could be detected at the lowest concentrations of either agent. At higher concentrations both agents impaired function, as indicated by an increase in reaction time, decreased ability to remember numbers, and decreased ability to assemble a simple structural array. Amnesia for word pairs but not pictures occurred at 27% of MAC for halothane and 18% of MAC for enflurane. All test scores reverted to control levels within one-half hour after discontinuing the anesthetic. Our results indicate that subanesthetic but not trace levels of enflurane or halothane can impair mental performance and manual dexterity and produce amnesia. The levels of anesthetic required far exceed those experienced by operating room personnel. However, such levels might be found for several hours in patients following prolonged anesthesia.
Awareness, defined as conscious memory during anesthesia, has been a problem in anesthesia practice. To determine the effect of isoflurane and nitrous oxide (N2O) on memory, 17 healthy adult volunteers were randomly assigned to receive isoflurane or N2O and received the alternate agent 1-2 weeks later. Each volunteer was studied at four end-tidal concentrations of each agent, consecutively 0.15, 0.3, 0.45, and 0.15 times the minimum alveolar concentration (MAC) for isoflurane or 0.3, 0.45, 0.6, and 0.3 times MAC for N2O. After 15-min equilibration at each end-tidal concentration, volunteers were tested for voluntary response to command and were presented with verbal information to be recalled after anesthesia. Volunteers were interviewed on the day after the study and tested for conscious and unconscious memory of the information presented during anesthetic administration. MAC-awake (the end-tidal concentration preventing voluntary response in 50% of volunteers) was 0.38 (0.35-0.42) times MAC for isoflurane and 0.64 (0.61-0.68) MAC for N2O (means, 95% confidence limits), indicating isoflurane to be more potent than N2O in suppressing voluntary response (P = .0001). Memory data were analyzed in 12 volunteers who completed the study and in whom the allocation of information to be recalled was counterbalanced among agents and concentrations of agents. Memory was decreased by increasing concentrations of both agents. Conscious memory of the information presented during anesthetic administration was prevented by 0.45 MAC isoflurane but not completely prevented by 0.6 MAC N2O. Unconscious memory (defined as memory of information without conscious recognition) occurred during administration of both agents and was prevented by 0.45 MAC isoflurane but not by 0.6 MAC N2O. Isoflurane was more potent in suppressing memory than MAC-equivalent concentrations of N2O. Using models of the relationship between dose of agent and suppression of memory, a dose of both agents was estimated that suppressed memory by 50% (ED50). The ED50 was 0.20 MAC for isoflurane (95% confidence intervals, 0.15-0.25), and 0.50 MAC for N2O (95% confidence intervals 0.43-0.55). We conclude that isoflurane and N2O suppress memory in a dose-dependent manner, and that isoflurane is more potent in preventing memory and voluntary response to command than MAC-equivalent concentrations of N2O.
The minimum alveolar concentration of anesthetic (MAC) necessary to prevent movement in response to a painful stimulus was relatively constant in dogs anesthetized with halothane. MAC varied over a two-fold range with the intensity of the stimulus, but appeared to reach an upper limit beyond which a further increase in intensity did not increase MAC. For the same stimulus MAC was constant from dog to dog. MAC was unaffected by duration of anesthesia, unaltered by hypocarbia or hypercarbia, by phenylephrine-in-duced hypertension or by mild hypoxia (Pao2 30 to 60 mm. of mercury). Hemorrhagic hypotension or marked acute metabolic acidosis reduced MAC by 10 to 20 per cent. Severe hypoxia (Pao2 less than 30 mm. of mercury) reduced MAC by 25 to 50 per cent.
Evidence concerning the concentrations of volatile anesthetics that prevent learning and recall is limited. Epinephrine is believed to enable learning during anesthesia. We investigated the effects of isoflurane and its interaction with epinephrine on learning and subsequent retention of the rabbit's classically conditioned nictitating membrane response.
In experiment 1, a tone (conditioned stimulus, CS) preceded paraorbital shock (unconditioned stimulus, US) during 60-min daily sessions of 60 presentations of these paired stimuli for 6 days of acquisition training under 0, 0.4%, or 0.8% isoflurane (n = 8, 13, and 9, respectively). Responses were recorded as conditioned responses (CRs) if they occurred during the CS and before the onset of the US. After 1 day of rest, the animals were given 3 days of extinction consisting of 60 presentations of CS-alone and without isoflurane to assess the retention of CRs from acquisition training. In experiment 2, epinephrine in a dose of 0, 0.01, or 0.1 mg/kg was injected subcutaneously in rabbits receiving 0.4% isoflurane. Two types of epinephrine were used, a sustained release form and epinephrine hydrochloride. Acquisition and retention were tested in the same way as in experiment 1. No isoflurane or epinephrine was used during retention testing.
Learning was significantly suppressed during 0.4% isoflurane (approximately equal to 0.2 MAC) treatment and eliminated during 0.8% (approximately equal to 0.4 MAC). Information learned during administration of 0.4% isoflurane was not retained (P < 0.05). Although the low doses of epinephrine improved learning during the last day of the acquisition phase (P < 0.05), there were no differences between the treatment groups on any of the remaining acquisition or extinction days.
There was no learning during treatment with 0.8% concentration. Even a 0.4% concentration, which allowed some learning, abolished CRs in extinction, perhaps because of state-dependent retrieval. Epinephrine did not alter substantially the rates of CR acquisition or resistance to extinction.
Nonanesthetic gases or vapors do not abolish movement in response to noxious stimuli despite partial pressures and affinities for lipids that would, according to the Meyer-Overton hypothesis, predict such abolition. We investigated whether nonanesthetics depress learning and memory (i.e., provide amnesia). To define learning, we used a "fear-potentiated startle paradigm": rats trained to associate light with a noxious stimulus (footshock) will startle more, as measured by an accelerometer, when a startle-eliciting stimulus (e.g., a noise) is paired with light than when the startle-eliciting stimulus is presented alone. We imposed light-shock pairings on 98 rats under three conditions: no anesthesia (control); 0.20, 0.29, and 0.38 times the minimum alveolar anesthetic concentration (MAC) of desflurane; or two nonanesthetics (1,2-dichloroperfluorocyclobutane and perfluoropentane) at partial pressures predicted from their lipid solubilities to be between 0.2 and 1 MAC. Desflurane produced a dose-related depression of learning with abolition of learning at 0.28 MAC. Perfluoropentane at 0.2-predicted MAC had the same effect as 0.28 MAC desflurane. 1,2-Dichloroperfluorocyclobutane at 0.5- to 1-predicted MAC abolished learning. Because nonanesthetics suppress learning but not movement (the two critical components of anesthesia), they may prove useful in discriminating between mechanisms and sites of action of anesthetics.
Transient neural injuries, such as asphyxia, can trigger considerable delayed neuronal death. Inappropriate induction of apoptosis is thought to play an important role in this process. Our studies have shown marked changes in the IGF system in the brain in response to these injuries with an induction of insulin growth factor (IGF)-1 and insulin growth factor binding protein (IGFBP)-2 and IGFBP-3 in glial cells in the region of injury. This suggests that the IGF-1 system may be an endogenous neuroprotective system. Earlier administration of IGF-1 - 2 h after injury reduced the phase of secondary neuronal loss suggesting that IGF-1 may well have therapeutic potential as a neuronal rescue agent. The action of IGF-1 appears to involve binding proteins, transport to the site of injury and the IGF-1 receptor and inhibition of apoptosis, but might also involve generation of GPE which itself appears to be neuroprotective. Together these results indicate considerable potential of these agents to treat stroke, perinatal asphyxia and other forms of acute brain injury.
Insulin-like growth factor-I (IGF-I) is a pleiotropic polypeptide with a wide range of actions in both central and peripheral nervous sytems. Over the past few years, we studied the trophic as well as neuromodulatory roles of IGF-I in the brain. Accumulated evidence indicates that IGF-I, apart from regulating growth and development, protects neurons against cell death induced by amyloidogenic derivatives, glucose or serum deprivation via the activation of intracellular pathways implicating phosphatidylinositide 3/Akt kinase, winged-helix family of transcription factor FKHRL1 phosphorylation or production of free radicals. The effects of IGF-I on neuroprotection, glucose metabolism and activity-dependent plasticity suggest the potential usefulness of this growth factor or related mimetics in the treatment of Alzheimer's disease and other neurodegenerative disorders.
Recent reports suggest that one type of learning, fear conditioning to context, requires more neural processing than a related type, fear conditioning to tone. To determine whether these types of learning were differentially affected by anesthesia, the authors applied isoflurane during the training phases of fear conditioning paradigms for freezing to context and freezing to tone.
The authors trained seven groups of eight rats to fear tone by administering a tone (conditioned stimulus) while breathing various concentrations of isoflurane from 0.00 to 0.75 minimum alveolar concentration (MAC; one concentration per group) separated by 0.12-MAC steps. On the succeeding day, and in the absence of isoflurane, the authors presented the tone (without shock) in a different context (different cage shape and odor) and measured the time each rat froze (became immobile). Six other groups of eight rats were trained to fear context by applying the shock in the absence of a tone but in the presence of environmental cues such as cage shape, texture, and odor. Fear to context was determined the succeeding day by returning the rat to the training cage (without shock) and measuring duration of freezing. Control groups (16 per group) received 0.75 MAC isoflurane but no foot shocks. Group scores were compared using analysis of variance, and the ED50 values for quantal responses of individual rats were calculated using logistic regression.
Conditioning to context occurred at 0.00 and 0.13 MAC (P < 0.05 compared with unshocked control) but not 0.25 MAC; the ED50 was 0.25 +/- 0.03 MAC (mean +/- SEM). In contrast, conditioning to tone occurred at 0.48 MAC (P < 0.05) but not 0.62 MAC; the ED50 was 0.47 +/- 0.02 MAC (P < 0.01 for the difference between ED50 values).
Suppression of fear conditioning to tone required approximately twice the isoflurane concentration that suppressed fear conditioning to context. Thus, the concentration of anesthetic required to suppress learning may depend on the neural substrates of learning. Our results suggest that isoflurane concentrations greater than 0.5 MAC may be needed to suppress both forms of fear conditioning.
Aging is characterized by a significant decline of metabolic and hormonal functions, which often facilitates the onset of severe age-associated pathologies. One outstanding example of this is the reported association of deranged signaling by insulin and insulin-like-growth-factor 1 (IGF-1) with Alzheimer's disease (AD). Recent compelling biological data reveal effects of insulin and IGF-1 on molecular and cellular mechanisms underlying the pathology of AD. This review discusses available biological data that highlight the therapeutic potential of the insulin-IGF-1 signaling pathway in AD.
Modern societies face new public health challenges associated with an increasingly aging population. Among these, pathological conditions linked to brain aging are paramount. Old age is a risk factor for important neurological impairments such as Alzheimer's disease or stroke. Even healthy elderly people usually present with milder forms of cognitive decline. This is possibly related to less-pronounced brain deficits seen in normal aging, including the shrinkage of neurons and the dense network of neurons and glia in the central nervous system known as the neuropil, a lower neurogenetic rate, impaired angiogenesis or brain accumulation of deleterious compounds. At least in mammals, age is also associated with a decline in insulin-like growth factor-I (IGF-I) levels, a well-known neuroprotective agent. Recently, a relationship between serum IGF-I and "house-keeping" mechanisms in the brain has been evidenced in laboratory rodents. Serum IGF-I increases adult neurogenesis, sustains neuronal health through a variety of fundamental homeostatic mechanisms, participates in brain angiogenesis, contributes to brain beta-amyloid clearance and affects learning and memory. Overall, diminished trophic input resulting from decreasing serum IGF-I levels during aging likely contributes to brain senescence in mammals.
Three mouse models of Alzheimer's disease (AD) were used to assess changes in gene expression potentially critical to amyloid beta-peptide (Abeta)-induced neuronal dysfunction. One mouse model harbored homozygous familial AD (FAD) knock-in mutations in both, amyloid precursor protein (APP) and presenilin 1 (PS-1) genes (APP(NLh/NLh)/PS-1(P264L/P264L)), the other two models harbored APP over-expression of FAD mutations (Tg2576) with the PS-1 knock-in mutation at either one or two alleles. These mouse models of AD had varying levels of Abeta40 and Abeta42 and different latencies and rates of Abeta deposition in brain. To assess changes in gene expression associated with Abeta accumulation, the Affymetrix murine genome array U74A was used to survey gene expression in the cortex of these three models both prior to and following Abeta deposition. Altered genes were identified by comparing the AD models with age-matched control littermates. Thirty-four gene changes were identified in common among the three models in mice with Abeta deposition. Among the up-regulated genes, three major classes were identified that encoded for proteins involved in immune responses, carbohydrate metabolism, and proteolysis. Down-regulated genes of note included pituitary adenylate cyclase-activating peptide (PACAP), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor I receptor (IGF-IR). In young mice without detectable Abeta deposition, there were no regulated genes common among the three models, although 40 genes were similarly altered between the two Tg2576 models with the PS-1 FAD knock-in. Finally, changes in gene expression among the three mouse models of AD were compared with those reported in human AD samples. Sixty-nine up-regulated and 147 down-regulated genes were found in common with human AD brain. These comparisons across different genetic mouse models of AD and human AD brain provide greater support for the involvement of identified gene expression changes in the neuronal dysfunction and cognitive deficits accompanying amyloid deposition in mammalian brain.
Tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-I (IGF-I) have been involved in the pathogenesis of Alzheimer's disease (AD) as neurotoxic and survival factors, respectively. Recent experimental studies suggest that the signalling pathways of TNF-alpha and IGF-I are functionally interrelated. In order to investigate the possible interaction of TNF-alpha and IGF-I in AD and mild cognitive impairment (MCI), the serum levels of total IGF-I, free IGF-I and TNF-alpha were determined in 141 AD patients, 56 MCI cases and 30 controls. As compared with controls, AD patients showed increased TNF-alpha and decreased IGF-I levels in serum, as well as a significant negative correlation between TNF-alpha and free IGF-I values. MCI patients also exhibited significantly higher TNF-alpha levels than controls. The present results suggest that increased TNF-alpha levels are involved in the pathogenesis of AD and MCI, and might antagonize the neurotrophic activity of IGF-I in these medical conditions. In addition, the combined determination of TNF-alpha and IGF-I might be useful to monitor anti-inflammatory and/or neurotrophic drug effects in AD.
Insulin resistance is a feature of a number of clinical disorders, including type 2 diabetes/glucose intolerance, obesity, dyslipidaemia and hypertension clustering in the so-called metabolic syndrome. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulin-stimulated glycogen synthesis due to reduced glucose transport. Ectopic lipid accumulation plays an important role in inducing insulin resistance. Multiple defects in insulin signalling are responsible for impaired glucose metabolism in target tissues of subjects with features of insulin resistance. Inflammatory molecules and lipid metabolites inhibit insulin signalling by stimulating a number of different serine kinases which are responsible for serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1).
The authors designed a prospective longitudinal study to investigate the hypothesis that advancing age is a risk factor for postoperative cognitive dysfunction (POCD) after major noncardiac surgery and the impact of POCD on mortality in the first year after surgery.
One thousand sixty-four patients aged 18 yr or older completed neuropsychological tests before surgery, at hospital discharge, and 3 months after surgery. Patients were categorized as young (18-39 yr), middle-aged (40-59 yr), or elderly (60 yr or older). At 1 yr after surgery, patients were contacted to determine their survival status.
At hospital discharge, POCD was present in 117 (36.6%) young, 112 (30.4%) middle-aged, and 138 (41.4%) elderly patients. There was a significant difference between all age groups and the age-matched control subjects (P < 0.001). At 3 months after surgery, POCD was present in 16 (5.7%) young, 19 (5.6%) middle-aged, and 39 (12.7%) elderly patients. At this time point, the prevalence of cognitive dysfunction was similar between age-matched controls and young and middle-aged patients but significantly higher in elderly patients compared to elderly control subjects (P < 0.001). The independent risk factors for POCD at 3 months after surgery were increasing age, lower educational level, a history of previous cerebral vascular accident with no residual impairment, and POCD at hospital discharge. Patients with POCD at hospital discharge were more likely to die in the first 3 months after surgery (P = 0.02). Likewise, patients who had POCD at both hospital discharge and 3 months after surgery were more likely to die in the first year after surgery (P = 0.02).
Cognitive dysfunction is common in adult patients of all ages at hospital discharge after major noncardiac surgery, but only the elderly (aged 60 yr or older) are at significant risk for long-term cognitive problems. Patients with POCD are at an increased risk of death in the first year after surgery.
Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.