Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basal Ganglia / pathology
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Cell Death / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Choline O-Acetyltransferase / metabolism
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Cyclic AMP / metabolism
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Excitatory Amino Acid Agonists / toxicity
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Excitatory Amino Acid Antagonists / toxicity*
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Exenatide
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Glial Fibrillary Acidic Protein / metabolism
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Glucagon / metabolism
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Glucagon / pharmacology*
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Glucagon-Like Peptide 1
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Glucagon-Like Peptide-1 Receptor
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Glutamic Acid / toxicity*
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Hippocampus / cytology
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Hippocampus / drug effects
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Ibotenic Acid / antagonists & inhibitors
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Ibotenic Acid / toxicity
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Immunohistochemistry
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Nerve Degeneration / chemically induced*
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Nerve Degeneration / prevention & control*
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Neurons / drug effects*
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Neurons / pathology
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Parasympathetic Nervous System / drug effects
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Peptides / pharmacology*
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Protein Precursors / metabolism
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Protein Precursors / pharmacology*
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Rats
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Rats, Inbred F344
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Rats, Sprague-Dawley
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Receptors, Glucagon / drug effects
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Receptors, Glucagon / metabolism
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Venoms*
Substances
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Glial Fibrillary Acidic Protein
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Peptide Fragments
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Peptides
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Protein Precursors
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Receptors, Glucagon
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Venoms
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Ibotenic Acid
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Glutamic Acid
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Glucagon-Like Peptide 1
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Glucagon
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Exenatide
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Cyclic AMP
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Choline O-Acetyltransferase