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Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA

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Abstract

Glucagon-like peptide-1 (GLP-1) is thought to preserve neurons and glia following axonal injury and neurodegenerative disorders. We investigated the neurotrophic and neuroprotective properties of exendin (Ex)-4, a synthetic GLP-1 receptor (GLP-1R) agonist, on adult rat dorsal root ganglion (DRG) neurons and PC12 cells. GLP-1R was predominantly localized on large and small peptidergic neurons in vivo and in vitro, suggesting the involvement of GLP-1 in both the large and small sensory fiber functions. Ex-4 dose-dependently (1 ≤ 10 ≤ 100 nM) promoted neurite outgrowth and neuronal survival at 2 and 7 days in culture, respectively. Treatment with 100 nM Ex-4 restored the reduced neurite outgrowth and viability of DRG neurons caused by the insulin removal from the medium and suppressed the activity of RhoA, an inhibitory regulator for peripheral nerve regeneration, in PC12 cells. Furthermore, these effects were attenuated by co-treatment with phosphatidylinositol-3′-phosphate kinase (PI3K) inhibitor, LY294002. These findings imply that Ex-4 enhances neurite outgrowth and neuronal survival through the activation of PI3K signaling pathway, which negatively regulates RhoA activity. Ex-4 and other GLP-1R agonists may compensate for the reduced insulin effects on neurons, thereby being beneficial for the treatment of diabetic neuropathy.

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Acknowledgments

This study was supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (Grant Number: 25430056) and the fund from Nukada Institute for Medical and Biological Research, Chiba, Japan. We thank Drs. Kazuhiko Watabe, Hitoshi Kawano, and Junji Yamauchi for their helpful suggestions, Dr. Yasuo Ohashi and Statcom Co., Ltd. for helpful comments on the statistical analyses, Emiko Kawakami, Hiroko Yanagisawa, and the late Kyoko Ajiki for technical assistance, and Enago (www.enago.jp) for the English language review.

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  1. Shizuka Takaku

    Present address: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8506, Japan

Authors and Affiliations

  1. Diabetic Neuropathy Project (Former Laboratory of Peripheral Nerve Pathophysiology), Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Masami Tsukamoto, Naoko Niimi, Kazunori Sango, Shizuka Takaku & Yasushi Kanazawa

  2. Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan

    Masami Tsukamoto, Yasushi Kanazawa & Kazunori Utsunomiya

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  1. Masami Tsukamoto
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  2. Naoko Niimi
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Correspondence to Kazunori Sango.

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Masami Tsukamoto and Naoko Niimi have contributed equally to this work.

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Tsukamoto, M., Niimi, N., Sango, K. et al. Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA. Histochem Cell Biol 144, 249–259 (2015). https://doi.org/10.1007/s00418-015-1333-3

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