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.
Braida
D
D
Institute of Pharmacology, Faculty of Mathematical, Physical and Natural Sciences, University of Milan, Italy.
Paladini
E
E
Griffini
P
P
Lamperti
M
M
Colibretti
L
L
Sala
M
M
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D007189:Indans / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013619:Tacrine / Q000627:therapeutic use
D002800:Cholinesterase Inhibitors; D007189:Indans; C099419:MF 268; D009025:Morpholines; D018727:Muscarinic Antagonists; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D012601:Scopolamine