Rho kinase inhibitor Y-27632 facilitates recovery from experimental peripheral neuropathy induced by anti-cancer drug cisplatin.
Chemotherapy drugs have neurotoxicity associated with treatment, which can become a dose-limiting problem when clinical presentation is severe. However, there is no effective therapy to circumvent the neurotoxicity of anti-cancer drug treatment. In this study, we utilized a newly designed mouse model of cisplatin-induced peripheral neuropathy to determine both the severity of neurotoxicity induced by drug treatment and the effectiveness of the Rho kinase inhibitor Y-27632 in post-treatment recovery. Sensory nerve conduction studies revealed a significant increase in mean distal (peak) latency with cisplatin treatment, indicating a deterioration of sensory nerve function. Also, hind paw touch sensitivity decreased steadily with increasing cumulative dose of cisplatin. Histological and immunohistochemical analyses of the sural nerve using neuronal marker protein gene product 9.5 (PGP 9.5) demonstrated abnormal nerve fiber morphology in cisplatin-treated mice. Remarkably, post-treatment with Y-27632 improved the sural nerve distal (peak) latency and sensory threshold to return to pre-treatment levels. Sural nerve histology worsened in the absence of Y-27632 during recovery. These studies suggest that Rho kinase inhibitor Y-27632 can initiate regeneration of damaged nerves following cisplatin treatment.
James
Sarah E
SE
Department of Anatomy and Cell Biology, Leo Jenkins Cancer Center, East Carolina University, Brody School of Medicine, 600 Moye Boulevard, Greenville, NC 27834, USA.
Dunham
Mayisha
M
Carrion-Jones
Monica
M
Murashov
Alexander
A
Lu
Qun
Q
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000627:therapeutic use*; D013497:Sural Nerve / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D055698:Touch Perception / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases; D002945:Cisplatin