Effect of a novel prolyl endopeptidase inhibitor, JTP-4819, on spatial memory and on cholinergic and peptidergic neurons in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis.
We conducted behavioral and neurochemical studies of a novel prolyl endopeptidase inhibitor, (S)2-[[(S)-2-(hydroxyacetyl)-1pyrrolidinyl]carbonyl]-N-(phenylmeth yl)-1-pyrrolidine-carboxamide (JTP-4819), in rats with lesions of the nucleus basalis magnocellularis (NBM-lesioned rats) induced by ibotenate. Administration of JTP-4819 (1 and 3 mg/kg, p.o.), on and after the 8th day, significantly shortened the escape latency in the Morris water maze as compared to the vehicle-treated group. JTP-4819 also significantly increased the path length in the quadrant with the platform removed in the spatial probe trial. Neurochemical studies of brains removed after the Morris water maze task showed that choline acetyltransferase activity in the cerebral cortex, but not the hippocampus, was significantly reduced by NBM lesioning, while there were no changes of muscarinic M1 receptor binding activity detected using [3H]pirenzepine. JTP-4819 had almost no effect on these cholinergic parameters in NBM-lesioned rats. Substance P-like immunoreactivity (LI), thyrotropin-releasing hormone (TRH)-LI, and arginine-vasopressin-LI were not significantly changed in the cerebral cortex and hippocampus of NBM-lesioned rats as compared to sham-operated rats. However, these neuropeptide levels were significantly increased in both brain regions by repeated administration of JTP-4819 (1, 3 and/or 10 mg/kg, p.o.). These results suggest that JTP-4819 ameliorated memory impairment due to NBM lesioning by potentiating SP, TRH and AVPergic neurons secondary to PEP inhibition.
Shinoda
M
M
Central Pharmaceutical Research Institute, Japan Tobacco, Takatsuki, Osaka.
Miyazaki
A
A
Toide
K
K
D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001479:Basal Ganglia / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D007051:Ibotenic Acid / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000166:cytology* / Q000187:drug effects*; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D009479:Neuropeptides; D011759:Pyrrolidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D015842:Serine Proteinase Inhibitors; D001127:Arginine Vasopressin; D007051:Ibotenic Acid; D013373:Substance P; D013973:Thyrotropin-Releasing Hormone; C094211:JTP 4819; D002795:Choline O-Acetyltransferase; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases