GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism

被引:488
作者
Li, Yazhou [1 ]
Perry, TracyAnn [1 ]
Kindy, Mark S. [2 ,3 ]
Harvey, Brandon K. [4 ]
Tweedie, David [1 ]
Holloway, Harold W. [1 ]
Powers, Kathleen [4 ]
Shen, Hui [4 ]
Egan, Josephine M. [5 ]
Sambamurti, Kumar [2 ]
Brossi, Arnold [6 ]
Lahiri, Debomoy K. [7 ]
Mattson, Mark P. [1 ]
Hoffer, Barry J. [8 ]
Wang, Yun [4 ]
Greig, Nigel H. [1 ]
机构
[1] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA
[2] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA
[3] Neurol Testing Serv, Mt Pleasant, SC 29466 USA
[4] Natl Inst Drug Abuse, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD 21224 USA
[5] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA
[6] Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA
[7] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA
[8] Natl Inst Drug Abuse, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA
关键词
diabetes; exendin-4; neurodegeneration; neuroprotection; stroke; GLUCAGON-LIKE PEPTIDE-1; CEREBELLAR GRANULE NEURONS; CYCLIC-AMP; DIABETES-MELLITUS; CEREBRAL-ISCHEMIA; ANIMAL-MODEL; APOPTOSIS; DEATH; RISK; BRAIN;
D O I
10.1073/pnas.0806720106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1285 / 1290
页数:6
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