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

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 vehicleinfused 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 passiveavoidance 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. Alzheimer’s disease (AD) is characterized by deterioration of cognitive function in aged humans. A major pathological hallmark of AD is extensive deposition of 39to 43-amino acid amyloid-! (A!), which is generated from a larger protein, the amyloid precursor protein (APP) (Glenner and Wong, 1984). Historically, the amyloid cascade hypothesis has been defined as the fibrillization of A! into amyloid deposits as a toxic gain of function (Hardy and Higgins, 1992). However, several lines of evidence have converged recently to show that the soluble A! oligomers rather than insoluble A! fibrils might produce cognitive dysfunction in AD (Hardy and Selkoe, 2002). First, soluble A! oligomers have been isolated from brain in human AD (Kuo et al., 1996). Second, transgenic mouse models that overexpress mutants or wild-type APP have shown that synaptic deficits correlate with increased levels of soluble A! rather than amyloid deposits (Mucke et al., 2000). Triple-transgenic mouse models harboring mutant PS1, APP, and tau show synaptic dysfunction, including long-term potentiation (LTP) deficits before the appearance of plaque and tangle pathology (Oddo et al., 2003). Third, it has been shown that A!1–42 This study was supported by a grant-in-aid for Science Research (no. 14370031), a COE Grant, and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Research Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.098640. ABBREVIATIONS: AD, Alzheimer’s disease; A!, amyloid-!; APP, amyloid precursor protein; LTP, long-term potentiation; GST, glutathione S-transferase; ChAT, choline acetyltransferase; ACh, acetylcholine; ZSET845, 3,3,-dibenzylimidazo[1,2-a]pyridin-2-(3H)-one; ZSET1446, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one; CMC, carboxymethyl cellulose; AChE, acetylcholinesterase; ANOVA, analysis of variance. 0022-3565/06/3173-1079–1087$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 317, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 98640/3108395 JPET 317:1079–1087, 2006 Printed in U.S.A.