Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats.
Methanesulfonyl fluoride (MSF), a highly selective CNS inhibitor of acetylcholinesterase, has been recently demonstrated to promote improvement in cognitive performance in patients with senile dementia of Alzheimer type. Because a similar cognitive impairment may accompany stroke, we investigated in the present study whether treatment with MSF could produce beneficial effects in adult rats subjected to an experimental stroke model. Sprague-Dawley rats received transient 60 min intraluminal occlusion of the right middle cerebral artery (MCAo) and were given i.p. injections of either MSF (1 mg/kg at 24 and 48 h post-MCAo and 0.3 mg/kg thereafter every other day) or the vehicle, peanut oil, for 4 weeks. Behavioral tests and biochemical assays were performed at 28 days post-surgery. MSF treatment produced about 90% inhibition of acetylcholinesterase in the brain. Ischemic animals that received the vehicle displayed significant elevated body swing biased activity (84.8 +/- 10%) and significantly prolonged acquisition (398 +/- 62 s) and shortened retention (79 +/- 26 s) of the passive avoidance task. Interestingly, while the ischemic animals that received the MSF exhibited elevated body swing biased activity (87.7 +/- 8%), they performed significantly better in the passive avoidance task (255 +/- 36 s and 145 +/- 18 s in acquisition and retention) than the vehicle-treated animals. Moreover, whereas brains from both groups of animals revealed similar extent and degree of cerebral infarction, the MSF-treated ischemic animals showed more intense immunoreactivity, as well as a significantly higher number (10-15% increase) of septal choline acetyltransferase-positive cells than the vehicle-treated ischemic animals. These results show that MSF, possibly by preserving a functional cholinergic system, attenuated stroke-induced deficits in a simple learning and memory task.
Borlongan
Cesario V
CV
National Institutes of Health, National Institute on Drug Abuse, Intramural, Research Program, Cellular Neurophysiology, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. cborlongan@mail.mcg.edu
Sumaya
Isabel C
IC
Moss
Donald E
DE
D000110:Acetylcholinesterase / Q000187:drug effects; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D002544:Cerebral Infarction / Q000150:complications / Q000201:enzymology* / Q000517:prevention & control; D002795:Choline O-Acetyltransferase / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003072:Cognition Disorders / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D008569:Memory Disorders / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D013450:Sulfones / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D013450:Sulfones; C005109:methanesulfonyl fluoride; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase