Abstract
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.
Footnotes
-
This work was supported by the Intramural National Institute on Aging (to T.P., J.Z., K.T.Y.S., J.M.E., and N.H.G.), National Institutes of Health Grant NIH-NIAR01, and grants from the Alzheimer's Association (to D.K.L. and D.C.).
- Abbreviations:
- CNS
- central nervous system
- GLP-1
- glucagon-like peptide-1 (7-36)-amide
- NGF
- nerve growth factor
- FBS
- fetal bovine serum
- PKA
- protein kinase A
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- BrdU
- 5′-bromo-2′-deoxy-uridine
- MTT
- 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
- LDH
- lactate dehydrogenase
- MTS
- 3-(4,5-dimethyl-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt
- ERK
- extracellular signal-regulated kinase
- MAP
- mitogen-activated protein
- PI3-kinase
- phosphatidylinositol 3-kinase
- Received October 8, 2001.
- Accepted November 26, 2001.
- U.S. Government
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
