Effects of metrifonate on memory impairment and cholinergic dysfunction in rats.
Metrifonate is an organophosphorous compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of metrifonate on the impairment of learning and on central cholinergic dysfunction in scopolamine-treated and basal forebrain-lesioned rats. Oral administration of metrifonate (5.0-15.0 mg/kg) ameliorated the scopolamine- and basal forebrain. lesion-induced learning impairment in the water maze and passive avoidance tasks. Metrifonate (50 and 100 mg/kg) also significantly increased extracellular acetylcholine levels but decreased choline levels in the cerebral cortex of the basal forebrain-lesioned rats. The basal forebrain lesion decreased the cholinesterase activity in the cerebral cortex, and metrifonate (100 mg/kg) further reduced the cholinesterase activity. However, cholinesterase inhibition was not observed at the dose that ameliorated learning impairments. These results indicated that metrifonate ameliorated the impairment of learning in both scopolamine-treated and basal forebrain-lesioned rats by not only increasing extracellular acetylcholine levels by inhibiting cholinesterase, but also by undefined other mechanism(s). This finding suggests the usefulness of metrifonate for the therapy of Alzheimer's disease.
Itoh
A
A
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Nitta
A
A
Katono
Y
Y
Usui
M
M
Naruhashi
K
K
Iida
R
R
Hasegawa
T
T
Nabeshima
T
T
D000109:Acetylcholine / Q000378:metabolism; D000647:Amnesia / Q000188:drug therapy; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D002802:Cholinesterases / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000523:psychology; D017551:Microdialysis; D016548:Prosencephalon / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D014236:Trichlorfon / Q000627:therapeutic use*
D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D014236:Trichlorfon; D012601:Scopolamine; D002802:Cholinesterases; D000109:Acetylcholine