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Research ArticleCELLULAR AND MOLECULAR

A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells

TracyAnn Perry, Debomoy K. Lahiri, Demao Chen, Jie Zhou, Karen T. Y. Shaw, Josephine M. Egan and Nigel H. Greig
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 958-966; DOI: https://doi.org/10.1124/jpet.300.3.958
TracyAnn Perry
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Debomoy K. Lahiri
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Demao Chen
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Jie Zhou
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Karen T. Y. Shaw
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Josephine M. Egan
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Nigel H. Greig
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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
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleCELLULAR AND MOLECULAR

A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells

TracyAnn Perry, Debomoy K. Lahiri, Demao Chen, Jie Zhou, Karen T. Y. Shaw, Josephine M. Egan and Nigel H. Greig
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 958-966; DOI: https://doi.org/10.1124/jpet.300.3.958

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Research ArticleCELLULAR AND MOLECULAR

A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells

TracyAnn Perry, Debomoy K. Lahiri, Demao Chen, Jie Zhou, Karen T. Y. Shaw, Josephine M. Egan and Nigel H. Greig
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 958-966; DOI: https://doi.org/10.1124/jpet.300.3.958
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