Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats.
Several studies have indicated the possibility of using cholinesterase (ChE) inhibitors as therapeutic drugs for Alzheimer's disease. Metrifonate (MTF) is an organophosphorus compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of MTF on the impairment of learning and memory, decreased ChE activity and extracellular acetylcholine (ACh) levels in basal forebrain (BF)-lesioned rats. The oral administration of MTF improved the BF-lesion-induced impairment of performance on passive avoidance task. Further, MTF reduced ChE activity in the cerebral cortex. In vivo brain microdialysis studies showed that MTF significantly increased the release of ACh, but decreased that of choline (Ch) in the cerebral cortex of BF-lesioned rats. These results indicated that MTF ameliorates the impairment of performance on passive avoidance task in BF-lesioned rats by increasing the extracellular ACh levels by inhibiting ChE. This suggested that MTF may be useful as a therapeutic drug for Alzheimer's disease.
Itoh
A
A
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Nitta
A
A
Hirose
M
M
Hasegawa
T
T
Nabeshima
T
T
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001479:Basal Ganglia / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D007859:Learning Disabilities / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014236:Trichlorfon / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D014236:Trichlorfon; D002802:Cholinesterases; D002794:Choline; D000109:Acetylcholine