|교육과학기술부·한국연구재단 지정 중점연구소
한림대학교 생명공학연구소 제2회 정기세미나
Department of Pathology School of Medicine University of California, San Francisco
Quinacrine is a potent anti-prion compound in cell culture models of prion disease. However, it has failed to show efficacy in mouse bioassays and human clinical trials possibly because of its poor pharmacokinetic properties. Given that quinacrine is known to be a substrate for Pglycoproteins, we decided to overcome its poor permeability across the blood brain barrier by utilizing MDR10/0 mice that are deficient of mdr1a and mdr1b genes. By treating these mice with 40 mg/kg/day of quinacrine for one month, we were able to achieve very high concentrations of quinacrine (up to 100 μM) in the brain without acute toxicity. Fluorescence microscopy showed that quinacrine was distributed throughout the brain. However, the treatment of prion inoculated MDR10/0 mice (initiated 60 days post inoculation (dpi) and continuing for one month) failed to extend survival. The results suggest that pharmacokinetics is not solely responsible for the failure of quinacrine in vivo.
We subsequently examined the levels of PrPSc during the course of quinacrine treatment. Surprisingly, we observed that PrPSc levels were greatly reduced during the course of treatment. This reduction was transient and PrPSc levels recovered rapidly after 15 days of treatment. We hypothesized that quinacrine clears a portion of the heterogeneous PrPSc population in the brain, and the remaining quinacrine-resistant PrPSc population rapidly proliferates with prolonged treatment. Consistent with this hypothesis, MDR10/0 mice continuously treated from 0 dpi, developed disease earlier than 30-days treated or untreated mice. PrPSc in quinacrine treated mice brains showed slight shifts in its conformational stability compared to the untreated control. Interestingly, we were able to reproduce this phenomenon in cultured cells utilizing differentiated PrP over-expressing, prion infected ScN2a/cl3 cells. Upon continuous quinacrine treatment, PrPSc levels are transiently reduced for three days, but rapidly recover afterwards. We propose that quinacrine eliminates a specific set of PrPSc conformers, resulting in the proliferation of drug resistant prion conformations. This phenomenon provides an explanation for that lack of in vivo efficacy of quinacrine in mouse models and human clinical trials.
중점연구소 생명공학연구소에서는 아래의 연사분을 초청하여 제 2회 정기세미나를 개최하오니
많은 참석 부탁드리겠습니다.
- 다 음-
1. 행사명 : 한림대학교 생명공학연구소 제2회 정기세미나
2. 일 시 : 2010. 02. 03(수) 11:00 ~ 11:50
3. 장 소 : 산학협력단 세미나실(12102호)
4. 연 사 : MI SOL AHN(안미솔) Email: firstname.lastname@example.org
1999 B.S. / University of Washington / Biochemistry/Chemistry
2007 Ph.D. / University of Washington / Pharmacology
2007~2008 Postdoctoral Fellow / University of California, San Francisco Institute for Neurodegenerative Diseases
2008~현재 Assistant Research Professional / Neuropharmacologist / Department of Pathology School of Medicine University
of California, SanFrancisco