GLP-1受体介导脑缺血保护作用的“记忆效应”及机理研究
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摘要
通过神经保护药物预防高危人群脑缺血发生至关重要。胰高血糖素样肽-1(GLP-1)受体是广泛分布于中枢神经系统的G蛋白偶联受体,我们前期研究首次发现激动GLP-1受体能够产生长时程的神经保护作用,在其激动剂exendin-4(Ex-4)停药6天进行脑缺血再灌注后仍然能够明显减少损伤后梗死体积,我们将其称之为GLP-1受体介导的保护性"记忆效应",然而其作用机制目前尚不清楚。我们针对这一现象展开深入研究,Ex-4停药后,PI3K/AKT信号通路及其下游分子p-mTOR和HIF-1α持续高表达,当立体定位注射shRNA沉默表达HIF-1α后,其"记忆效应"消失,提示该效应由PI3K/AKT/mTOR/HIF-1信号通路介导。
引文
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2.Gaede P,Vedel P,Larsen N,Jensen GV,Parving HH,et al.(2003)Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med 348:383-393.
3.Sander D,Kearney MT(2009)Reducing the risk of stroke in type 2 diabetes:pathophysiological and therapeutic perspectives.J Neurol 256:1603-1619.
4.Drab SR(2015)Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes:A Clinical Update of Safety and Efficacy.Curr Diabetes Rev.
5.Dong YF,Wang LX,Huang X,Cao WJ,Lu M,et al.(2013)Kir6.1 knockdown aggravates cerebral ischemia/reperfusion-induced neural injury in mice.CNS Neurosci Ther 19:617-624.
6.Zhang H,Meng J,Li X,Zhou S,Qu D,et al.(2015)Pro-GLP-1,a Pro-drug of GLP-1,is neuroprotective in cerebral ischemia.Eur J Pharm Sci 70:82-91.
7.Voll CL,Auer RN(1991)Insulin attenuates ischemic brain damage independent of its hypoglycemic effect.J Cereb Blood Flow Metab 11:1006-1014.
8.Auer RN(1998)Insulin,blood glucose levels,and ischemic brain damage.Neurology 51:S39-43.