The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease.
The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease.
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DOI：
10.1186/s40478-017-0456-2
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发表时间：
2017-06-28
影响因子：
7.1
通讯作者：
Cherny RA
中科院分区：
文献类型：
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作者：
Finkelstein DI;Billings JL;Adlard PA;Ayton S;Sedjahtera A;Masters CL;Wilkins S;Shackleford DM;Charman SA;Bal W;Zawisza IA;Kurowska E;Gundlach AL;Ma S;Bush AI;Hare DJ;Doble PA;Crawford S;Gautier EC;Parsons J;Huggins P;Barnham KJ;Cherny RA
SNPC中铁升高可能在帕金森病(PD)神经退行性变中起关键作用，因为具有高铁亲和力的候选药物拯救PD动物模型，其中一种候选药物deferirpone最近在第二阶段临床试验中显示出疗效。然而，强大的铁络合剂可能会扰乱基本的铁代谢，目前尚不清楚与铁相关的损害是由紧密结合的铁蛋白(如铁蛋白)或低亲和力、不稳定的铁池介导的。在这里，我们报告了PBT434的临床前特征，这是一种新型的喹唑烷酮化合物，具有中等亲和力的金属结合基序，正在开发中，用于帕金森病。在体外，PBT434在降低细胞铁水平方面远不如去铁酮或去铁胺有效，但却被发现抑制了铁介导的氧化还原活性和铁介导的α-突触核蛋白的聚集，这是一种聚集在神经病理中的蛋白质。在体内，PBT434没有耗尽正常啮齿动物的组织铁储存，但防止了黑质致密部神经元的丢失，降低了黑质α-突触核蛋白的积聚，并挽救了暴露于帕金森病毒素6-OHDA和MPTP的小鼠以及帕金森病转基因动物模型(hA53Tα-突触核蛋白)的运动能力。这些改善与氧化损伤标志物的减少以及铁转运蛋白(一种铁出口物质)和DJ-1水平的提高有关。我们的结论是，针对组织中不存在于高亲和力复合体中的病理性铁池而设计的化合物可以维持SNPC神经元的存活，并可能对帕金森病起到改善疾病的作用。本文的在线版本(doi：10.1186/s40478-0170456-2)包含补充材料，授权用户可以使用。
Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD. The online version of this article (doi:10.1186/s40478-017-0456-2) contains supplementary material, which is available to authorized users.