Evaluation of quinacrine treatment for prion diseases
Evaluation of quinacrine treatment for prion diseases
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DOI：
10.1128/jvi.77.15.8462-8469.2003
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发表时间：
2003-08-01
影响因子：
5.4
通讯作者：
Deslys, JP
中科院分区：
文献类型：
--
作者：
Barret, A;Tagliavini, F;Deslys, JP
根据对瘙痒症感染的神经母细胞瘤细胞的体外观察，奎纳克林最近被提议用于治疗克雅氏病 (CJD)，包括一种新的 CJD 变体，该变体与牛海绵状脑病 (BSE) 制剂污染食物有关。本研究调查了奎纳克林对朊病毒的可能作用机制。分析了奎纳克林与人和动物来源的 PrP 肽聚集体和 PrPres 相互作用并降低其蛋白酶抗性的能力，以及其抑制正常朊病毒蛋白 (PrPc) 体外转化为异常形式 (PrPres) 的能力。此外，在不同的体外模型和 BSE 实验鼠模型中检查了奎纳克林和另一种三环化合物氯丙嗪的功效。奎纳克林有效地阻碍了 ScN2a 细胞中纤维化朊病毒蛋白的从头生成和 PrPres 积累。然而，它无法影响脑匀浆中预先存在的 PrP 原纤维和 PrPres 的蛋白酶抗性，并且只有在长时间处理后才能在 ScGT1 细胞中获得“治愈”效果。在体内，在所使用的动物模型中没有观察到可检测到的影响，这与其他最近的研究和人类的初步观察结果一致。尽管奎纳克林能够穿过血脑屏障，但使用奎纳克林治疗克雅氏病还是值得怀疑的，至少作为单一疗法是这样。这里采用的多步骤实验方法可用于在用于人体试验之前测试新的治疗方案。
Based on in vitro observations in scrapie-infected neuroblastoma cells, quinacrine has recently been proposed as a treatment for Creutzfeldt-jakob disease (CJD), including a new variant CJD which is linked to contamination of food by the bovine spongiform encephalopathy (BSE) agent. The present study investigated possible mechanisms of action of quinacrine on prions. The ability of quinacrine to interact with and to reduce the protease resistance of PrP peptide aggregates and PrPres of human and animal origin were analyzed, together with its ability to inhibit the in vitro conversion of the normal prion protein (PrPc) to the abnormal form (PrPres). Furthermore, the efficiencies of quinacrine and chlorpromazine, another tricyclic compound, were examined in different in vitro models and in an experimental murine model of BSE. Quinacrine efficiently hampered de novo, generation of fibrillogenic prion protein and PrPres accumulation in ScN2a cells. However, it was unable to affect the protease resistance of preexisting PrP fibrils and PrPres from brain homogenates, and a "curing" effect was obtained in ScGT1 cells only after lengthy treatment. In vivo, no detectable effect was observed in the animal model used, consistent with other recent studies and preliminary observations in humans. Despite its ability to cross the blood-brain barrier, the use of quinacrine for the treatment of CJD is questionable, at least as a monotherapy. The multistep experimental approach employed here could be used to test new therapeutic regimes before their use in human trials.