Kinoshita K, Watanabe Y, Yamamura M, Matsuoka Y
Pharmaceutical Development Res. Lab., Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Eur J Pharmacol. 1998 Feb 19;343(2-3):129-33. doi: 10.1016/s0014-2999(97)01539-2.
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.
研究了促甲状腺激素释放激素（TRH）受体激动剂对3-乙酰吡啶诱导的大鼠小脑共济失调的影响。3-乙酰吡啶显著降低垂直跳跃的最大高度，并伴有运动不协调。新型TRH类似物TA-0910（（-）-N-[(S)-六氢-1-甲基-2,6-二氧代-4-嘧啶基羰基]-L-组氨酰-L-脯氨酰胺四水合物；0.3-3mg/kg）和TRH（10和30mg/kg）单次腹腔注射后，均能显著提高被抑制的垂直跳跃最大高度。这些药物的作用在给药后1小时达到峰值，24小时后消失。腹腔注射NMDA受体拮抗剂MK-801（10,11-二氢-5-甲基-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐；0.1mg/kg）预处理可完全抵消TA-0910（1mg/kg）和TRH（10mg/kg）诱导的垂直跳跃最大高度增加。荷包牡丹碱、蝇蕈醇、巴氯芬、赛庚啶和哌唑嗪均不影响TRH受体激动剂的作用。总之，在改善小脑功能障碍方面，TA-0910比TRH更有效。这些TRH受体激动剂的抗共济失调作用可能由3-乙酰吡啶处理的大鼠中的NMDA受体介导。
