Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on thyrotropin-releasing hormone-like immunoreactivity in the cerebral cortex and hippocampus of aged rats.
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.
Shinoda
M
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Okamiya
K
K
Toide
K
K
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013973:Thyrotropin-Releasing Hormone / Q000187:drug effects*
D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013973:Thyrotropin-Releasing Hormone; C094211:JTP 4819