Prevention of Prion Propagation by Dehydrocholesterol Reductase Inhibitors in Cultured Cells and a Therapeutic Trial in Mice(Biopharmacy)

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In prion diseases, the normal cellular form of prion protein (PrP^c) is converted into the disease-associated isoforms (PrP^<Sc>) which accumulate in the infected tissues. Although the precise mechanism of this conversion remains unsolved, drugs of various categories have been reported to reduce the accumulation of PrP^<Sc> in prion-infected cultured cells. We here show that AY-9944 (a 7-dehydrocholesterol reductase inhibitor) and U18666A (a 24-dehydrocholesterol reductase inhibitor) prevent PrP^<Sc> from accumulating in prion-infected mouse neuroblastoma cells (ScN2a), with an ED_<50> of about 0.5μM and 10 nM, respectively. In order to evaluate the efficacy of these two inhibitors in vivo, C57BL/6J mice inoculated with mouse-adapted scrapie-prion received repetitive intraperitoneal injections of U18666A (lOmg/kg) or a mixture of U18666A (lOmg/kg) and AY-9944 (12mg/kg). By contrast to the potent anti-prion effects observed in ScN2a cells, the in vivo trial was abortive with neither drug halting the progression of the disease.
公益社団法人日本薬学会の論文
2007-04-01