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Vol. 302, Issue 3, 881-888, September 2002

Protection and Reversal of Excitotoxic Neuronal Damage by Glucagon-Like Peptide-1 and Exendin-4

TracyAnn Perry, Norman J. Haughey, Mark P. Mattson, Josephine M. Egan and Nigel H. Greig

Section of Drug Design and Development (T.A.P., N.H.G.) and Section of Cellular and Molecular Neuroscience (N.J.H., M.P.M.), Laboratory of Neuroscience and Diabetes Section, Laboratory of Clinical Investigation (J.M.E.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland

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.

0022-3565/02/3023-0881$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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