Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4.
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.
Section of Drug Design and Development, Laboratory of Neuroscience, Gerontology Research Center, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. perryt@grc.nia.nih.gov
TracyAnn
T
Perry
Norman J
NJ
Haughey
Mark P
MP
Mattson
Josephine M
JM
Egan
Nigel H
NH
Greig
D000818:Animals; D001479:Basal Ganglia / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D000077270:Exenatide; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007051:Ibotenic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010275:Parasympathetic Nervous System / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000187:drug effects / Q000378:metabolism; D014688:Venoms
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; D007051:Ibotenic Acid; D018698:Glutamic Acid; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D000242:Cyclic AMP; D002795:Choline O-Acetyltransferase