Antiamnesic effects of azaindolizinone derivative ZSET845 on impaired learning and decreased ChAT activity induced by amyloid-beta 25-35 in the rat.
Antiamnesic effects of a newly synthesized azaindolizinone derivative ZSET845 were assessed in rats made learning ability deficient by amyloid-beta (Abeta)25-35 treatment. Intracerebroventricular injection of Abeta25-35 induced a marked decrease in step-through latency in passive avoidance task and reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex. The number of ChAT-immunoreactive cells was decreased in the medial septum. Oral administration of ZSET845 at a dose of 1 or 10 mg/kg ameliorated learning impairment in passive avoidance task and enhanced ChAT activity in the basal forebrain, medial septum and hippocampus, and increased in the number of ChAT-immunoreactive cells in the medial septum in Abeta-treated rats to the levels of vehicle-injected control rats. These results suggest that ZSET845 is worth testing for further preclinical study aimed for the treatment of senile dementia such as Alzheimer's disease.
Yamaguchi
Yoshimasa
Y
Research Laboratory, Zenyaku Kogyo Co., Ltd., 2-33-7 Ohizumi-machi, Nerima-ku, Tokyo 178-0062, Japan. Yoshimasa_ Yamaguchi@mail.zenyaku.co.jp
Matsuno
Toshiyuki
T
Kawashima
Seiichiro
S
D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D007150:Immunohistochemistry; D007858:Learning / Q000187:drug effects*; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011597:Psychomotor Performance / Q000187:drug effects; D011728:Pyridones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
C464538:(3,3-dibenzylimidazo(1,2-a)pyridin-2-(3H)-one); D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011728:Pyridones; C074636:amyloid beta-protein (25-35); D002795:Choline O-Acetyltransferase