title: RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice.
abstract: Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies.
authors.affiliation: Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Megumi
authors.initials: M
authors.lastname: Aasato
authors.forename: Shun-Suke
authors.initials: SS
authors.lastname: Hayashi
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D003176:Complement C3 / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019821:Simvastatin / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D003176:Complement C3; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C108830:Y 27632; D009569:Nitric Oxide; D013311:Streptozocin; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein