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      Effect of Oxidative Stress on the Uptake of GABA and Glutamate in Synaptosomes Isolated from Diabetic Rat Brain

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          It has been suggested that increased oxidative stress might be involved in the pathophysiology of diabetic complications. In this study, we investigated the effect of diabetes on the susceptibility of synaptosomes to oxidative stress (induced by the oxidizing pair ascorbate/Fe<sup>2+</sup>) and on the uptake of the amino acid neurotransmitters γ-aminobutyric acid (GABA) and glutamate. We found a lower susceptibility of synaptosomes isolated from Goto-Kakizaki (GK) rats, a model of non-insulin-dependent diabetes mellitus, to lipid peroxidation as compared with synaptosomes isolated from Wistar control rats (6.40 ± 1.05 and 12.14 ± 1.46 nmol thiobarbituric acid reactive substance/mg protein, respectively). The lower susceptibility of GK rat synaptosomes to membrane lipid peroxidation correlates with an increase in synaptosomal vitamin E levels (835 ± 58.04 and 624.26 ± 50.26 pmol/mg protein in diabetic and normal rats, respectively). In the absence of ascorbate/Fe<sup>2+</sup>, no significant differences were observed between the levels of lipid peroxidation of synaptosomes isolated from diabetic and normal rats. Studies of neurotransmitter uptake show that the [<sup>3</sup>H]glutamate uptake was decreased by about 30% in diabetic GK rats as compared with control Wistar rats, whereas the [<sup>3</sup>H]GABA uptake was not significantly different from controls. Under oxidizing conditions, the glutamate uptake in diabetic rats was unaffected, and a decreased GABA uptake (41.39 ± 4.41 and 60.96 ± 6.4% of control in GK and Wistar rats, respectively) was observed. We conclude that the increased resistance to oxidative stress in GK rat synaptosomes may be due to the increased vitamin E content and that diabetic state and oxidative stress conditions differentially affected the uptake of the neurotransmitters GABA and glutamate.

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          Most cited references 12

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          A radical hypothesis for neurodegeneration.

           C.W. Olanow (1993)
          Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.
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            Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes.

            Glucose has been found to improve memory in animals and humans. Animal research has revealed that glucose may improve memory through a facilitation of acetylcholine (ACh) synthesis and release in the brain. This glucose-related memory improvement has prompted research in elderly humans. These studies have shown that the memory-improving action of glucose depends on each individuals' blood glucose regulation. Based on these data, researchers have evaluated the effect of glucose on memory in patients with Alzheimer's disease (AD). Results demonstrated that glucose could improve memory in a subset of patients that had abnormalities in their blood glucose regulation. Interestingly, these alterations in blood glucose regulation were believed to depend on the severity of the disease process. Another line of investigation has focused on alterations in brain glucose metabolism. Both animal models and studies with Type II diabetic elderly patients have shown that altered glucose regulation impairs learning and memory processes. It is possible that in AD patients, hyperglycemia exerts a deleterious effect by potentiating the neuronal death produced by other pathological processes taking place such as amyloid deposition. Based on these data, it appears important to find the prevalence of altered glucoregulation at various stages of AD. Secondly, it may be of interest to determine prospectively whether altered glucoregulation is linked to a faster progression of the disease. Finally, if such a relationship is observed, the next logical step would be to determine whether AD patients could benefit from treatments aimed at normalizing blood glucose regulation and improving insulin sensitivity.
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                Author and article information

                S. Karger AG
                September 2000
                27 September 2000
                : 72
                : 3
                : 179-186
                aCenter for Neurosciences of Coimbra, and bDepartment of Zoology and cFaculty of Medicine, University of Coimbra, Portugal
                54585 Neuroendocrinology 2000;72:179–186
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 53, Pages: 8
                Hormone Actions on the Brain


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