Prevention of prion propagation by dehydrocholesterol reductase inhibitors in cultured cells and a therapeutic trial in mice.
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 ED50 of about 0.5 microM 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 (10 mg/kg) or a mixture of U18666A (10 mg/kg) and AY-9944 (12 mg/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.
Hagiwara
Ken'ichi
K
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Japan. hagiwark@nih.go.jp
Nakamura
Yuko
Y
Nishijima
Masahiro
M
Yamakawa
Yoshio
Y
D000736:Androstenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009447:Neuroblastoma / Q000821:virology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D011328:Prions / Q000187:drug effects*; D012608:Scrapie / Q000188:drug therapy* / Q000401:mortality*; D015996:Survival Rate; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D000736:Androstenes; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018620:PrPSc Proteins; D011328:Prions; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride