Pharmacological studies of a novel prolyl endopeptidase inhibitor, JTP-4819, in rats with middle cerebral artery occlusion.
We studied behavioral and pharmacological effects of a novel prolyl endopeptidase inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)- 1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidine-car boxamide (JTP-4819), in rats with middle cerebral artery occlusion. Administration of JTP-4819 (0.1 and 1 mg/kg p.o for 7 days) significantly prolonged passive avoidance latency, while the latency of rats with middle cerebral artery occlusion receiving the vehicle was significantly shorter than that of sham-operated rats. The prolonged escape latency in the Morris water maze task in rats with middle cerebral artery occlusion was also significantly reduced by administration of JTP-4819 (0.3 and 1 mg/kg p.o.). Interestingly, administration of JTP-4819 (0.3-3 mg/kg p.o. for 15 days) restored the decreased cortical thyrotropin-releasing hormone (TRH)-like immunoreactivity content of rats with middle cerebral artery occlusion but did not affect the cortical and hippocampal substance P- or arginine vasopressin-like immunoreactivity content. These results suggest that JTP-4819 ameliorates memory impairment due to middle cerebral artery occlusion by restoring the cortical TRH content.
Shinoda
M
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Matsuo
A
A
Toide
K
K
D000818:Animals; D001127:Arginine Vasopressin / Q000032:analysis; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000503:physiopathology*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology; D002536:Cerebral Arteries; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D006624:Hippocampus / Q000737:chemistry / Q000473:pathology; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000032:analysis; D013973:Thyrotropin-Releasing Hormone / Q000032:analysis
D011480:Protease Inhibitors; D011759:Pyrrolidines; D001127:Arginine Vasopressin; D013373:Substance P; D013973:Thyrotropin-Releasing Hormone; C094211:JTP 4819