Li Yazhou, Perry TracyAnn, Kindy Mark S, Harvey Brandon K, Tweedie David, Holloway Harold W, Powers Kathleen, Shen Hui, Egan Josephine M, Sambamurti Kumar, Brossi Arnold, Lahiri Debomoy K, Mattson Mark P, Hoffer Barry J, Wang Yun, Greig Nigel H
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1285-90. doi: 10.1073/pnas.0806720106. Epub 2009 Jan 21.
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD.
胰高血糖素样肽-1（GLP-1）是一种内源性促胰岛素肽，在摄入食物后从胃肠道分泌。它可增强胰岛β细胞增殖和葡萄糖依赖性胰岛素分泌，并降低2型糖尿病（T2DM）患者的血糖和食物摄入量。长效GLP-1受体（GLP-1R）激动剂艾塞那肽-4（Ex-4）是首批被批准用于治疗T2DM的这类新型抗高血糖药物。GLP-1R与环磷酸腺苷（cAMP）第二信使途径偶联，并且除胰腺细胞外，在啮齿动物和人类的神经系统中也有表达，受体激活在该系统中引发神经营养作用。我们在培养的胚胎原代大脑皮质和腹侧中脑（多巴胺能）神经元中均检测到了GLP-1R信使核糖核酸（mRNA）表达。这些细胞分别易受缺氧和6-羟基多巴胺诱导的细胞死亡影响。我们发现GLP-1和Ex-4对这些细胞具有保护作用，但对来自Glp1r基因敲除（-/-）小鼠的细胞则没有保护作用。在短暂性大脑中动脉闭塞性中风模型中，给予Ex-4可减少脑损伤并改善功能结局。在帕金森病（PD）的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中，Ex-4治疗还可保护多巴胺能神经元免于退化，维持多巴胺水平，并改善运动功能。我们的研究结果表明，Ex-4可保护神经元免受代谢和氧化损伤，并为Ex-4在治疗中风和PD方面的治疗潜力提供临床前支持。
