Ameliorating effect of rovatirelin on the ataxia in rolling mouse Nagoya

Abstract

Rovatirelin is a newly synthetized thyrotropin-releasing hormone (TRH) analog. This study aimed to investigate the effect of rovatirelin on motor function using rolling mouse Nagoya (RMN), a mouse model of hereditary ataxia, and compare it with that of taltirelin, which is clinically used to treat spinocerebellar degeneration in Japan. We also examined the effect of rovatirelin on glucose metabolism in various brain regions of RMN using autoradiography (ARG). Rovatirelin (1, 3, 10, and 30 mg/kg) dose-dependently reduced the fall index in RMN, and its effect was more potent than that of taltirelin (3, 10, 30, and 100 mg/kg). No attenuation of the effect was observed by repeated daily administration for 2 weeks. Furthermore, the reduction in the fall index by rovatirelin persisted for 2 weeks after completing treatment. In the ARG study, rovatirelin induced a significantly elevated uptake of glucose in the prefrontal cortex, nucleus accumbens shell, nucleus accumbens core, striatum, anterior cingulate cortex, secondary motor area, pretectal area, ventral tegmental area, black pars compacta, locus coeruleus, nucleus cerebellaris middle nucleus, medial nucleus of the vestibular nerve, fourth/fifth lobule, and third lobule. Furthermore, rovatirelin increased cerebellar mRNA level of brain derived neurotrophic factor. These results suggest that rovatirelin activates the cerebellum and other parts of the central nervous system to improve motor function in spinocerebellar ataxia (SCA) model animals, and its action is more potent than that of taltirelin. Therefore, rovatirelin can be a potential alternative to the traditionally used therapeutics for SCA.