Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4
Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4
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DOI：
10.1124/jpet.102.037481
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发表时间：
2002-09-01
影响因子：
3.5
通讯作者：
Greig, NH
中科院分区：
文献类型：
--
作者：
Perry, T;Haughey, NJ;Greig, NH
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，由胃肠道L细胞对食物产生应答而分泌。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效作用。在2型糖尿病中，GLP-1通过连续输注可以使血糖正常化，目前正在临床试验中作为这种疾病的治疗方法进行测试。最近，已发现GLP-1具有中枢神经系统（CNS）作用并刺激培养细胞中的神经突生长。我们现在报道GLP-1及其长效类似物exendin-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细胞凋亡。将这些作用外推至明确的啮齿动物神经变性模型，GLP-1和毒蜥外泌肽-4大大降低了鹅膏蕈氨酸诱导的基底前脑胆碱能神经元胆碱乙酰转移酶免疫反应性耗竭。这些发现鉴定了GLP-1的新的神经保护/神经营养功能，并表明这些肽可能具有停止或逆转CNS疾病（例如阿尔茨海默病）和与2型糖尿病相关的神经病变中的神经变性过程的潜力。
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.