Shinoda M, Okamiya K, Toide K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Jpn J Pharmacol. 1995 Nov;69(3):273-6. doi: 10.1254/jjp.69.273.
We investigated the effects of a novel prolyl endopeptidase inhibitor, JTP-4819 ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N- (phenylmethyl)-1-pyrrolidinecarboxamide), on thyrotropin-releasing hormone (TRH)-like immunoreactivity (TRH-LI) in the cerebral cortex and hippocampus of aged rats. The TRH-LI content of both brain regions in aged rats was significantly lower than that in young rats. A single oral dose of JTP-4819 (3 mg/kg) restored the cortical TRH-LI content in aged rats, while doses of 0.3-3 mg/kg restored it in the hippocampus. Repeated oral administration of JTP-4819 at a dose of 1 mg/kg for 21 days produced a significant increase of TRH-LI in the cerebral cortex, while it did so in the hippocampus at doses of 0.3 and 1 mg/kg. Our findings suggest that JTP-4819 may improve the functioning of TRHergic neurons, which deteriorate with senescence.
我们研究了一种新型脯氨酰内肽酶抑制剂JTP-4819（(S)-2-[[(S)-2-(羟基乙酰基)-1-吡咯烷基]羰基]-N-(苯基甲基)-1-吡咯烷甲酰胺）对老年大鼠大脑皮层和海马中促甲状腺激素释放激素（TRH）样免疫反应性（TRH-LI）的影响。老年大鼠这两个脑区的TRH-LI含量均显著低于年轻大鼠。单次口服JTP-4819（3毫克/千克）可使老年大鼠大脑皮层的TRH-LI含量恢复正常，而0.3 - 3毫克/千克的剂量可使海马中的TRH-LI含量恢复正常。以1毫克/千克的剂量重复口服JTP-4819 21天，可使大脑皮层中的TRH-LI显著增加，而0.3和1毫克/千克的剂量可使海马中的TRH-LI显著增加。我们的研究结果表明，JTP-4819可能改善随着衰老而退化的TRH能神经元的功能。
