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Vol. 300, Issue 3, 958-966, March 2002
Section of Drug, Design, and Development, Laboratory of
Neuroscience (T.P., K.T.Y.S., N.H.G.) and Diabetes Section, Laboratory
of Clinical Investigation (J.Z., J.M.E.), Gerontology Research Center,
National Institute on Aging, National Institutes of Health, Baltimore,
Maryland; and Institute of Psychiatric Research, Indiana University
School of Medicine, Indianapolis, Indiana (D.K.L., D.C.)
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.
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