A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells.
The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.
Perry
TracyAnn
T
Section of Drug, Design, and Development, Laboratory of Neuroscience, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. perryt@grc.nia.nih.gov
Lahiri
Debomoy K
DK
Chen
Demao
D
Zhou
Jie
J
Shaw
Karen T Y
KT
Egan
Josephine M
JM
Greig
Nigel H
NH
D000595:Amino Acid Sequence; D000818:Animals; D000963:Antimetabolites; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D000077270:Exenatide; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000473:pathology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D018027:Receptors, Glucagon / Q000096:biosynthesis; D013268:Stimulation, Chemical; D013778:Tetrazolium Salts; D013844:Thiazoles; D014688:Venoms
D000963:Antimetabolites; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D013778:Tetrazolium Salts; D013844:Thiazoles; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D020932:Nerve Growth Factor; D000077270:Exenatide; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D001973:Bromodeoxyuridine