Chronic anti-ataxic actions of the novel thyrotropin-releasing hormone (TRH) analog, TA-0910, during and after repeated administration in Rolling mouse Nagoya: behavioral and pharmacokinetic studies.
Anti-ataxic effects of TA-0910, a novel thyrotropin-releasing hormone analog, in mice of the ataxic mutant mouse strain Rolling mouse Nagoya (RMN) are sustained beyond its 2-week oral administration period (Kinoshita et al., Eur. J. Pharmacol., 274, 65-72, 1995). We examined the concentration of TA-0910 in the central nervous system (CNS) of RMN after repeated administration in an attempt to clarify the mechanism of the sustained effect of the drug. Repeated administration of TA-0910 (3 mg/kg/d, i.p.) for 2 weeks produced a long-lasting ameliorating effect on ataxia in RMN, and this effect was maintained until 3 weeks after drug withdrawal. The concentrations of TA-0910 in the cerebrum and brain stem 24 h after the final administration were twice the concentration observed 24h after single administration. The cerebellum cencentration of TA-0910 was more than 4 times that observed 24 h after final administration. After repeated administrations, the drug concentrations in the brain tissues gradually decreased, but the drug was still detectable in the cerebrum and brain stem 3 weeks after withdrawal. However, these concentrations of TA-0910 3 weeks after withdrawal were as low those observed 24 h after single administration when there were no anti-ataxic effects. These observations suggest that the long-lasting ameliorating effect on the ataxia during and after repeated administration of TA-0910 is not ascribable to the drug remaining in the CNS of RMN.
Kinoshita
K
K
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda-shi, Saitama, Japan.
Fukushima
T
T
Kodama
Y
Y
Sugihara
J
J
Yamamura
M
M
Matsuoka
Y
Y
D000818:Animals; D001259:Ataxia / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018697:Nootropic Agents / Q000494:pharmacology*; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D018697:Nootropic Agents; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone