Continuous quinacrine treatment results in the formation of drug-resistant prions.
Continuous quinacrine treatment results in the formation of drug-resistant prions.
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DOI：
10.1371/journal.ppat.1000673
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发表时间：
2009-11
期刊：
影响因子：
6.7
通讯作者：
Prusiner SB
中科院分区：
文献类型：
--
作者：
Ghaemmaghami S;Ahn M;Lessard P;Giles K;Legname G;DeArmond SJ;Prusiner SB
奎纳克林是一种在朊病毒疾病细胞培养模型中有效的抗朊病毒化合物，但在动物生物测定和人体临床试验中未能显示出功效。先前的研究表明，奎纳克林无法有效地穿透血脑屏障（BBB），这可能导致其在体内缺乏功效。由于奎纳克林已知是 P-糖蛋白多药耐药性 (MDR) 转运蛋白的底物，因此我们通过利用缺乏 mdr1a 和 mdr1b 基因的 MDR0/0 小鼠来规避其较差的 BBB 通透性。每天接受 40 毫克/公斤奎纳克林治疗的小鼠，其大脑中积累了高达 100 µM 的奎纳克林，且没有急性毒性。在开始奎纳克林治疗后，接种朊病毒的 MDR0/0 小鼠大脑中的 PrPSc 水平下降。然而，这种降低是暂时的，尽管持续服用奎纳克林，PrPSc 水平仍恢复。与未治疗的小鼠相比，奎纳克林治疗并没有延长接种朊病毒的野生型或 MDR0/0 小鼠的存活时间。在培养的分化的朊病毒感染的神经母细胞瘤细胞中观察到类似的现象：奎纳克林治疗后PrPSc水平最初下降，然后在连续治疗3天后迅速恢复。经奎纳克林治疗的小鼠大脑中持续存在的 PrPSc 的生化特征与未经治疗的对照小鼠大脑中发现的相比，具有较低的构象稳定性和不同的免疫亲和力。这些物理特性在 MDR0/0 小鼠传代后并未保持。根据这些数据，我们提出奎纳克林消除了 PrPSc 构象异构体的特定子集，从而导致耐药朊病毒构象的存活。这种耐药朊病毒群体的短暂积累为奎纳克林和其他抗朊病毒药物缺乏体内功效提供了可能的解释。朊病毒病属于神经退行性疾病，包括阿尔茨海默病、帕金森病和亨廷顿病。在每种疾病中，大脑中的特定蛋白质都会改变形状并积累，导致神经元损失和损伤。经过一段时间的神经退行性变、痴呆和运动功能障碍后，这些疾病都是致命的。奎纳克林是一种抗疟药，能够消除培养物中分裂细胞中的朊病毒，但对患病小鼠和人类患者无效。在这里，我们对这次失败进行了解释。我们的数据表明，服用奎纳克林会导致耐药朊病毒的增殖。这一见解将使我们能够在未来开发出更有效的抗朊病毒疗法。
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 µM 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 characterization of PrPSc that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR0/0 mice. From these data, we propose that quinacrine eliminates a specific subset of PrPSc conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs. Prion diseases belong to the class of neurodegenerative disorders that include Alzheimer, Parkinson and Huntington diseases. In each of these disorders, a specific protein in the brain changes shape and accumulates, leading to neuronal loss and damage. These diseases are uniformly fatal after a period of neurodegeneration, dementia and motor dysfunction. Quinacrine, an antimalarial drug, is able to eliminate prions from dividing cells in culture, yet is ineffective in diseased mice and human patients. Here, we provide an explanation for this failure. Our data indicate that the administration of quinacrine results in the proliferation of drug-resistant prions. This insight will enable us to develop more effective antiprion therapeutics in the future.
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影响因子：
4
作者：
Dohgu, S;Yamauchi, A;Kataoka, Y
通讯作者：
Kataoka, Y
影响因子：
5.4
作者：
Doh-Ura, K;Iwaki, T;Caughey, B
通讯作者：
Caughey, B
DOI：
10.1073/pnas.161274798
发表时间：
2001-08-14
影响因子：
11.1
作者：
Korth, C;May, BCH;Prusiner, SB
通讯作者：
Prusiner, SB
影响因子：
5.4
作者：
Doh-Ura, K;Ishikawa, K;Iwaki, T
通讯作者：
Iwaki, T
影响因子：
5.4
作者：
Kawasaki, Yuri;Kawagoe, Keiichi;Doh-ura, Katsurni
通讯作者：
Doh-ura, Katsurni