Perry TracyAnn, Haughey Norman J, Mattson Mark P, Egan Josephine M, Greig Nigel H
Section of Drug Design and Development, Laboratory of Neuroscience, Gerontology Research Center, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. doi: 10.1124/jpet.102.037481.
Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the L cells of the gastrointestinal tract in response to food. It has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation. In type 2 diabetes, GLP-1, by continuous infusion, can normalize blood glucose and is presently being tested in clinical trials as a therapy for this disease. More recently, GLP-1 has been found to have central nervous system (CNS) effects and to stimulate neurite outgrowth in cultured cells. We now report that GLP-1, and its longer-acting analog exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis. Extrapolating these effects to a well defined rodent model of neurodegeneration, GLP-1 and exendin-4 greatly reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in basal forebrain cholinergic neurons. These findings identify a novel neuroprotective/neurotrophic function of GLP-1 and suggest that such peptides may have potential for halting or reversing neurodegenerative processes in CNS disorders, such as Alzheimer's disease, and in neuropathies associated with type 2 diabetes mellitus.
胰高血糖素样肽-1（7-36）酰胺（GLP-1）是一种内源性促胰岛素肽，它在进食后从胃肠道的L细胞分泌。它对葡萄糖依赖性胰岛素分泌、胰岛素基因表达和胰岛细胞形成具有强大作用。在2型糖尿病中，持续输注GLP-1可使血糖正常化，目前正在临床试验中作为该疾病的一种治疗方法进行测试。最近，已发现GLP-1具有中枢神经系统（CNS）效应，并能刺激培养细胞中的神经突生长。我们现在报告，GLP-1及其长效类似物艾塞那肽-4可以完全保护培养的大鼠海马神经元免受谷氨酸诱导的凋亡。将这些效应外推到一个明确的神经退行性变啮齿动物模型中，GLP-1和艾塞那肽-4大大减少了鹅膏蕈氨酸诱导的基底前脑胆碱能神经元中胆碱乙酰转移酶免疫反应性的消耗。这些发现确定了GLP-1的一种新的神经保护/神经营养功能，并表明此类肽可能具有在中枢神经系统疾病（如阿尔茨海默病）以及与2型糖尿病相关的神经病变中阻止或逆转神经退行性变过程的潜力。
