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.