| Objective:Nowadays, relationship between diabetes mellitus and neurodegeneration disease has been generally recognized. GLP-1 analogue is a drug for diabetes treatment and its efficacy in neuroprotection is attracting attention. In this study, we aim to explore the protective effects of GLP-1 receptor agonist Exenatide on cognitive dysfunction of STZ-induced(Streptozocin, STZ) diabetic rats and its possible mechanism. Methods:Male Sprague-Dawley(SD) rats were divided into 3 groups randomly as following after a week of adaptive feeding: normal control(NC) group, diabetic mellitus(DM) group and Exenatide treatment(Ex+DM) group. Rats in DM group and Ex+DM group were fed with high fat and high glucose diet for 4 weeks and then were injected intraperitoneally with STZ(30mg/kg). The rats in NC group were injected with the same amount of citric acid buffer. Tail vein blood glucose was measured after 3 days of injection. After established the diabetic model successfully, rats in Ex+DM group were treated with Exenatide(3ug/kg, bid) for 16 weeks. Food and water intake, body weight and blood glucose were measured every week. At the end of the 21 weeks, cognitive function of rats was detected by Morris water maze test. Blood was collected for measurement of lipids and blood glucose. Hematoxylin-eosin staining was performed to analyze the hippocampal histopathological damage, the ultrastructure of hippocampal in rats was observed by transmission electron microscopy. The rest of samples were frozen and stored at-80 for assays.℃ Results:1 Water and food intake was increased while the body weight was decreased in DM group, compared with NC group. However, these abnormalities were ameliorated in Ex+DM group, compared with DM group. Body weight of Ex+DM group was lighter than the other 2 groups after 16 weeks treatment(P<0.05).2 Escape latencies of DM group in place navigation test of MWM were longer than NC group and Ex+DM group(P<0.05). Times of cross-platform of DM group in space exploration test of MWM were less than NC group and Ex+DM group(P<0.05). Outcomes of escape latencies and times of cross-platform were improved in Ex+DM group, compared with DM group(P<0.05).3 The blood glucose in DM group and Ex+DM group was increased than NC group. Level of TC and TG in DM group were higher than NC group and Ex+DM group(P<0.05).4 Structure of neuron and synaptic structure of hippocampus were partly damaged in DM group, but the abnormalities were attenuated in Ex+DM group.5 Total tau protein expression of hippocampus among 3 groups showed no statistical difference. The expression of phosphorylated tau protein(p-tau(s202) and p-tau(s396)) in DM group was greater than NC group and Ex+DM group(P<0.05). Tau protein phosphoration attenuated in Ex+DM group(P<0.05).6 MDA was increased in DM group compared to NC and Ex+DM group(P<0.05), SOD and GSH-PX activity was down regulated in DM group(P<0.05). These changes in Ex+DM group were less(P<0.05) than in DM group. Conclusion:Oxidative stress and the level of phosphorylated tau are increased in STZ-induced diabetic rats. GLP-1 receptor agonist Exenatide may improve diabetes related cognitive dysfunction by attenuating oxidative stress and tau phosphoralation of hippocampus in STZ-induced diabetic rats. |
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