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

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 β-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 dia...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-01, Vol.106 (4), p.1285-1290
Main Authors: 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
Format: Article
Language:English
Subjects:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Animals
Apoptosis
Biological Sciences
Brain
Brain Infarction - drug therapy
Brain Infarction - pathology
Cell death
Cell Death - drug effects
Cell Hypoxia - drug effects
Cells, Cultured
Cerebral Cortex - cytology
Cytoprotection - drug effects
Disease Models, Animal
Dopamine - metabolism
Dopaminergic neurons
Embryo, Mammalian - cytology
Gene Expression Regulation - drug effects
Glucagon-Like Peptide-1 Receptor
Humans
Hypoxia
Mesencephalon - cytology
Mice
Motor ability
Neurons
Neurons - drug effects
Neurons - pathology
Parkinson Disease - drug therapy
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson's disease
Peptides
Peptides - pharmacology
Peptides - therapeutic use
Rats
Receptors
Receptors, Glucagon - genetics
Receptors, Glucagon - metabolism
Rodents
Stroke
Stroke - drug therapy
Stroke - metabolism
Stroke - pathology
Strokes
Treatment Outcome
Venoms - pharmacology
Venoms - therapeutic use
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Summary: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 β-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0806720106