Long-lasting antiamnesic effect of a novel anticholinesterase inhibitor (MF268)

In the present study a short (120 min) and long-lasting (360 min) antagonism of scopolamine-induced amnesia in rats was investigated in an eight-arm radial maze, by (3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-o l[8-(cis2,6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate (MF268), a new cholinesterase inhibitor. Upon completing the training session, the rats were orally administered increasing doses of MF268 (2, 3, 6, 7, and 8 mg/kg) 60 min prior to s.c. injection of scopolamine (0.25 mg/kg). Following a further 60 min the rat was placed in the maze. The reversal of scopolamine-induced impairment was characterized by an inverted U-shaped dose-response curve. A significant reduction in the number of errors, and time taken to complete the maze was observed with a dose of 6 mg/kg. The compound improved memory retention without affecting scopolamine-induced hypermotility. When the same dose was administered 360 min prior to the test a significant reduction in the number of amnesic animals was observed, whereas no cognitive improvement was detected when either 1-Benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine hydrochloride (E2020) (0.25 mg/kg) or tacrine (0.5 mg/kg) were administered 360 min prior to the test. The kinetics of whole-brain cholinesterase confirmed the long-lasting activity for MF268. A clinical relevance for the use of MF268 in AD treatment is suggested.