title: The Rho-kinase inhibitor fasudil restores normal motor nerve conduction velocity in diabetic rats by assuring the proper localization of adhesion-related molecules in myelinating Schwann cells.
abstract: The Rho/Rho-kinase signaling pathway has been shown to be involved in the complications of diabetes. In this study, we found that fasudil, a specific Rho-kinase inhibitor, had a beneficial effect on the motor nerve conduction velocity (MNCV), which is delayed in rats with streptozotocin (STZ)-induced diabetes. Cadherin-dependent adherens junctions (AJs) in myelinating Schwann cells, necessary for proper myelin formation and rapid propagation of action potentials, are regulated by Rho/Rho-kinase signaling. These AJ structures are maintained by E-cadherin and catenin complexes such as β-catenin and p120 catenin. To elucidate the mechanism underlying the effect of fasudil on MNCV, we examined alterations in AJ structure in the peripheral nerves of the experimental rats. Our results showed that the activities of Rho and Rho-kinase increased simultaneously in the sciatic nerves of the diabetic rats. Fasudil restored the MNCV by suppressing the up-regulation of the Rho-kinase. In the diabetic state, enhanced Rho and Rho-kinase activity reduced p120 catenin expression and altered the distribution of p120 catenin and E-cadherin, which are normally localized in the paranodal compartment of the nodes of Ranvier and Schmidt-Lanterman incisures where autotypic AJs stabilize myelin structure. Fasudil restored normal p120 catenin expression and the distribution of p120 catenin and E-cadherin in the myelin sheath. In conclusion, reduced expression and altered distribution of the adhesion molecules in the myelin sheath might contribute to the slowing of the MNCV in the diabetic rats. Fasudil, through its effect on the distribution of the adhesion-related molecules, might prevent slowing of the MNCV.
authors: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Japan.
authors: Yasushi
authors: Y
authors: Kanazawa
authors: Junko
authors: J
authors: Takahashi-Fujigasaki
authors: Sho
authors: S
authors: Ishizawa
authors: Naoko
authors: N
authors: Takabayashi
authors: Kumiko
authors: K
authors: Ishibashi
authors: Keiichiro
authors: K
authors: Matoba
authors: Daiji
authors: D
authors: Kawanami
authors: Tamotsu
authors: T
authors: Yokota
authors: Naoko
authors: N
authors: Tajima
authors: Kazunori
authors: K
authors: Utsunomiya
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012234:Rho Factor / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology; D051176:beta Catenin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D012234:Rho Factor; D051176:beta Catenin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil; D000095002:Delta Catenin; C000722355:Ctnnd1 protein, rat
keywords: AJ; Adherens junction; Diabetic neuropathy; E-cadherin; Fasudil; MNCV; Motor nerve conduction velocity; Rho-kinase; STZ; Schmidt–Lanterman incisures; Streptozotocin; p120 catenin; p120 ctn