TRH receptor agonists ameliorate 3-acetylpyridine-induced ataxia through NMDA receptors in rats.
The effects of thyrotropin-releasing hormone (TRH) receptor agonists were examined on 3-acetylpyridine-induced cerebellar ataxia in rats. 3-acetylpyridine markedly decreased the maximal height of vertical jump, accompanied by motor incoordination. Both TA-0910 ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-L- histidyl-L-prolinamide tetrahydrate; 0.3-3 mg/kg), a novel TRH analog, and TRH (10 and 30 mg/kg) significantly increased the suppressed maximal height of vertical jump after single intraperitoneal administration. The effects of these drugs reached a maximum at 1 h and disappeared 24 h after administration. Both the TA-0910 (1 mg/kg)- and TRH (10 mg/kg)-induced increases in the maximal height of vertical jump were completely counteracted by pretreatment with i.p. injected MK-801 (10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; 0.1 mg/kg), an NMDA receptor antagonist. Neither bicuculline, muscimol, baclofen, cyproheptadine nor prazosin affected the effect of the TRH receptor agonists. In conclusion, TA-0910 is more potent than TRH in ameliorating cerebellar functional disorders. The anti-ataxic effects of these TRH receptor agonists may be mediated by NMDA receptors in 3-acetylpyridine-treated rats.
Kinoshita
K
K
Pharmaceutical Development Res. Lab., Tanabe Seiyaku Co., Ltd., Saitama, Japan. k-kino@tanabe.co.jp
Watanabe
Y
Y
Yamamura
M
M
Matsuoka
Y
Y
D000818:Animals; D002524:Cerebellar Ataxia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009536:Niacinamide / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology
D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D018025:Receptors, Thyrotropin-Releasing Hormone; C010835:3-acetylpyridine; C065049:TA 0910; D009536:Niacinamide; D013973:Thyrotropin-Releasing Hormone