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-β 1-40 in the rat

Yoshimasa Yamaguchi, Hitoshi Miyashita, Hiroko Tsunekawa, Akihiro Mouri, Hyoung Chun Kim, Kenichi Saito, Toshiyuki Matsuno, Seiichiro Kawashima, Toshitaka Nabeshima

Research output: Contribution to journalArticle

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Abstract

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-β (Aβ) 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 Aβ 1-40 or scopolamine. The i.c.v. infusion of Aβ 1-40 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. Aβ 1-40 -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 Aβ 1-40 -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 Aβ 1-40 -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 Aβ 1-40 - 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.

Original languageEnglish
Pages (from-to)1079-1087
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number3
DOIs
Publication statusPublished - 01-06-2006
Externally publishedYes

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Nootropic Agents
Amyloid
Learning
Intraventricular Infusions
Scopolamine Hydrobromide
Choline O-Acetyltransferase
Glutathione Transferase
Nicotine
Acetylcholine
Hippocampus
Avoidance Learning
Water
Memory Disorders
spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one
Short-Term Memory
Cholinergic Agents
Oral Administration
Alzheimer Disease
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Yamaguchi, Yoshimasa ; Miyashita, Hitoshi ; Tsunekawa, Hiroko ; Mouri, Akihiro ; Kim, Hyoung Chun ; Saito, Kenichi ; Matsuno, Toshiyuki ; Kawashima, Seiichiro ; Nabeshima, Toshitaka. / 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-β 1-40 in the rat In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 3. pp. 1079-1087.
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abstract = "We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid-β (Aβ) 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 Aβ 1-40 or scopolamine. The i.c.v. infusion of Aβ 1-40 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. Aβ 1-40 -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 Aβ 1-40 -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 Aβ 1-40 -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 Aβ 1-40 - 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.",
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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-β 1-40 in the rat . / Yamaguchi, Yoshimasa; Miyashita, Hitoshi; Tsunekawa, Hiroko; Mouri, Akihiro; Kim, Hyoung Chun; Saito, Kenichi; Matsuno, Toshiyuki; Kawashima, Seiichiro; Nabeshima, Toshitaka.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 3, 01.06.2006, p. 1079-1087.

Research output: Contribution to journalArticle

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