TY - JOUR
T1 - Effects of metrifonate on memory impairment and cholinergic dysfunction in rats
AU - Itoh, Akio
AU - Nitta, Atsumi
AU - Katono, Yuki
AU - Usui, Miho
AU - Naruhashi, Kazumasa
AU - Iida, Ryuichi
AU - Hasegawa, Takaaki
AU - Nabeshima, Toshitaka
N1 - Funding Information:
We are grateful to Bayer Yakuhin, Ltd. for supplying metrifonate. This work was partly supported by an SRF Grant for Biomedical Research, by Grants-in-Aid for Scientific Research from Ministry of Education, Science, and Culture of Japan (Nos. 07557009 and 07557303) and a Grant for Gerontological Science Research from the Ministry of Health and Welfare of Japan (No. 94A-2405).
PY - 1997/3/12
Y1 - 1997/3/12
N2 - 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.
AB - 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.
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U2 - 10.1016/S0014-2999(96)00977-6
DO - 10.1016/S0014-2999(96)00977-6
M3 - Article
C2 - 9088864
AN - SCOPUS:0030931020
VL - 322
SP - 11
EP - 19
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -