title: Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA.
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.
authors.affiliation: 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.
authors.forename: Masami
authors.initials: M
authors.lastname: Tsukamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Niimi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sango
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takaku
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Utsunomiya
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D000077270:Exenatide; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D007328:Insulin / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010455:Peptides / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D014688:Venoms / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D002867:Chromones; D007328:Insulin; D009025:Morpholines; D018696:Neuroprotective Agents; D010455:Peptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018027:Receptors, Glucagon; D014688:Venoms; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D020742:rhoA GTP-Binding Protein