Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on prolyl endopeptidase activity and substance P- and arginine-vasopressin-like immunoreactivity in the brains of aged rats.
The effects of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl) - 1-pyrrolidinecarboxamide (JTP-4819), on the PEP activity in the brain and on the contents of substance P (SP)- and arginine-vasopressin (AVP)-like immunoreactivity (LI) in the cerebral cortex and hippocampus of young and aged rats were investigated using enzyme immunoassay. JTP-4819 exhibited a concentration-dependent in vitro inhibitory action on PEP activity in the brains of both young and aged rats, with IC50 values of approximately 0.7 and 0.8 nM, respectively. A single dose of JTP-4819 (3 mg/kg, p.o.) increased the SPLI content in the cerebral cortex but not the hippocampus of aged rats (23-24 months old). In addition, repeated administration of JTP-4819 (1 mg/kg, p.o., for 21 days) increased the SPLI content in the cerebral cortex and restored the SPLI content in the hippocampus, which had decreased with aging. In contrast, single (1 mg/kg, p.o.) and repeated (1 mg/kg, p.o., for 21 days) administration of JTP-4819 only tended to increase the AVPLI content of the hippocampus and cerebral cortex in aged rats, respectively. These results indicate that JTP-4819 increases the cerebral and hippocampal SPLI content in aged rats by inhibiting the action of PEP.
Toide
K
K
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka.
Okamiya
K
K
Iwamoto
Y
Y
Kato
T
T
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D010703:Phorbol Esters / Q000737:chemistry / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism*
D004224:Diterpenes; D010703:Phorbol Esters; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; C094212:phorbol 12,13-dibenzoate 20-homovanillylamide; C094213:resiniferatoxin amide; D001127:Arginine Vasopressin; D013373:Substance P; C094211:JTP 4819; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases