THE THERAPEUTIC EFFECT OF RHO KINASE INHIBITOR Y-27632 ON PROTECTION FROM CHEMOTHERAPY INDUCED PERIPHEAL NEUROPATHY IN MOUSE MODEL

Abstract

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. Sensory nerve conduction studies revealed a significant increase in mean distal latency with cisplatin treatment, indicating a deterioration of sensory nerve function. Also, hind paw touch sensitivity decreased steadily with increasing cumulative dose of cisplatin. Von Frey analysis indicated a protective effect in mice treated with Y-27632. Histological and immunohistochemical analyses of the sural nerve using neuronal marker protein gene product s100 and CGRP demonstrated abnormal nerve fiber morphology in cisplatin-treated mice, but not in those treated with Y-27632. These studies suggest that Rho kinase inhibitor Y-27632 can ameliorate the damage caused by cisplatin in sensory related nerves but has no effect in nociceptor nerve endings.