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NEUROPHARMACOLOGY

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-_1–40 in the Rat

Research Laboratory, Zenyaku Kogyo Co., Ltd., Tokyo, Japan (Y.Y., H.M., K.S., T.M., S.K.); Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan (H.T., A.M., T.N.); and Neurotoxicology Program, Department of Pharmacy, College of Pharmacy, Kangwon National University, Korea Institute of Drug Abuse, Chunchon, South Korea (H.-C.K.)

We have previously shown that intracerebroventricular (i.c.v.) infusion of amyloid- (A)_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 A_1–40 or scopolamine. The i.c.v. infusion of A_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. A_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 A_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 A_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 A_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.

Address correspondence to: Dr. Yoshimasa Yamaguchi, Research Laboratory, Zenyaku Kogyo Co., Ltd., 2-33-7 Ohizumi-machi, Nerima-ku, Tokyo 178-0062, Japan. E-mail: yoshimasa_yamaguchi{at}mail.zenyaku.co.jp

This article has been cited by other articles:

				F. Han, N. Shioda, S. Moriguchi, Y. Yamamoto, A. Y. A. Raie, Y. Yamaguchi, M. Hino, and K. Fukunaga Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) Treatment Rescues Olfactory Bulbectomy-Induced Memory Impairment by Activating Ca2+/Calmodulin Kinase II and Protein Kinase C in Mouse Hippocampus J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 127 - 134. [Abstract] [Full Text] [PDF]

				Y. Ito, K. Takuma, H. Mizoguchi, T. Nagai, and K. Yamada A Novel Azaindolizinone Derivative ZSET1446 (Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) Improves Methamphetamine-Induced Impairment of Recognition Memory in Mice by Activating Extracellular Signal-Regulated Kinase 1/2 J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 819 - 827. [Abstract] [Full Text] [PDF]