1. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4.
- Author
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Perry T, Haughey NJ, Mattson MP, Egan JM, and Greig NH
- Subjects
- Animals, Basal Ganglia pathology, Cell Death drug effects, Cell Survival drug effects, Cells, Cultured, Choline O-Acetyltransferase metabolism, Cyclic AMP metabolism, Excitatory Amino Acid Agonists toxicity, Exenatide, Glial Fibrillary Acidic Protein metabolism, Glucagon metabolism, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Hippocampus cytology, Hippocampus drug effects, Ibotenic Acid antagonists & inhibitors, Ibotenic Acid toxicity, Immunohistochemistry, Neurons pathology, Parasympathetic Nervous System drug effects, Peptide Fragments metabolism, Protein Precursors metabolism, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Receptors, Glucagon drug effects, Receptors, Glucagon metabolism, Excitatory Amino Acid Antagonists toxicity, Glucagon pharmacology, Glutamic Acid toxicity, Nerve Degeneration chemically induced, Nerve Degeneration prevention & control, Neurons drug effects, Peptide Fragments pharmacology, Peptides pharmacology, Protein Precursors pharmacology, Venoms
- 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.
- Published
- 2002
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