Effects of a novel cognitive enhancer, spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on learning impairments induced by amyloid-beta1-40 in the rat.

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-beta (Abeta)1-40 produces oxidative stress and cholinergic dysfunction, as well as learning and memory deficits, in rats. In the present study, effects of a newly synthesized azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), were assessed in rats with learning deficits induced by Abeta1-40 or scopolamine. The i.c.v. infusion of Abeta1-40 caused impairments in spontaneous alternation behavior in a Y-maze task, spatial reference and short-term memory in a water-maze task, and retention of passive-avoidance learning. Abeta1-40-infused rats also showed reduction in choline acetyltransferase (ChAT) activity in the medial septum and hippocampus, but not in the basal forebrain and cortex, and a decrease in glutathione S-transferase (GST)-like immunoreactivity in the cortex. Nicotine-stimulated acetylcholine (ACh) release in Abeta1-40-infused rats was lower than that in vehicle-infused rats. Oral administration of ZSET1446 at the dose range of 0.01 to 1 mg/kg ameliorated Abeta1-40-induced learning impairment in Y-maze, water-maze, and passive-avoidance tasks. ZSET1446 reversed the decrease of ChAT activity in the medial septum and hippocampus, GST-like immunoreactivity in the cortex, and nicotine-stimulated ACh release of Abeta1-40-treated rats to the levels of vehicle-infused control rats. Furthermore, 0.001 to 0.1 mg/kg ZSET1446 showed ameliorative effects on learning impairments caused by scopolamine in a passive-avoidance task. These results suggest that ZSET1446 may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimer's disease.
AuthorsYoshimasa Yamaguchi, Hitoshi Miyashita, Hiroko Tsunekawa, Akihiro Mouri, Hyoung-Chun Kim, Kenichi Saito, Toshiyuki Matsuno, Seiichiro Kawashima, Toshitaka Nabeshima
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 317 Issue 3 Pg. 1079-87 (Jun 2006) ISSN: 0022-3565 [Print] United States
PMID16474004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • Indans
  • Peptide Fragments
  • Spiro Compounds
  • amyloid beta-protein (1-40)
  • spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one
  • Scopolamine Hydrobromide
  • Choline O-Acetyltransferase
  • Administration, Oral
  • Amyloid beta-Peptides (toxicity)
  • Animals
  • Behavior, Animal (drug effects)
  • Blotting, Western
  • Brain (drug effects, enzymology)
  • Choline O-Acetyltransferase (metabolism)
  • Cognition (drug effects)
  • Indans (administration & dosage, pharmacology, therapeutic use)
  • Injections, Intraventricular
  • Learning Disorders (chemically induced, drug therapy, physiopathology)
  • Male
  • Maze Learning (drug effects)
  • Memory (drug effects)
  • Motor Activity (drug effects)
  • Peptide Fragments (toxicity)
  • Rats
  • Rats, Wistar
  • Scopolamine Hydrobromide (toxicity)
  • Spiro Compounds (administration & dosage, pharmacology, therapeutic use)

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