continuous quinacrine treatment results in the formation of drug-resistant prions连续奎纳克林治疗导致朊病毒耐药的形成.pdfVIP

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions Sina Ghaemmaghami1,2., Misol Ahn3., Pierre Lessard1,2, Kurt Giles1,2, Giuseppe Legname1,2¤, Stephen J. DeArmond1,3, Stanley B. Prusiner1,2* 1 Institute for Neurodegenerative Diseases, University of California, San Francisco, California, United States of America, 2 Department of Neurology, University of California, San Francisco, California, United States of America, 3 Department of Pathology, University of California, San Francisco, California, United States of America Abstract Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P- glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR0/0 mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 mM of quinacrine in their brains without acute toxicity. PrPSc levels in the brains of prion-inoculated MDR0/0 mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrPSc levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR0/0 mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrPSc levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterizat