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.