Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson's disease
Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson's disease
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DOI：
10.1093/brain/awv184
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发表时间：
2015-09-01
期刊：
影响因子：
14.5
通讯作者：
Farde, Lars
中科院分区：
文献类型：
--
作者：
Jucaite, Aurelija;Svenningsson, Per;Farde, Lars
氧化应激与帕金森氏症的神经退化有关。Jucaite等人。研究表明，AZD3241--一种活性氧生酶髓过氧化物酶的抑制剂--在患者中减少了PET配体[C-11]PBR28与小胶质标记转位蛋白的结合。髓过氧化物酶抑制可能具有减少神经炎症和减缓疾病进展的潜力。氧化应激与帕金森病的神经退行性变有关。Jucaite等人。研究表明，AZD3241--一种活性氧生酶髓过氧化物酶的抑制剂--在患者中减少了PET配体[C-11]PBR28与小胶质标记转位蛋白的结合。髓过氧化物酶抑制可能具有减轻神经炎症和减缓疾病进展的潜力。线粒体功能障碍、氧化应激和过量的活性氧物种的形成在帕金森病的神经退行性变中起着关键作用。髓过氧化物酶是一种活性氧产生酶，由小胶质细胞表达。新型化合物AZD3241是一种选择性的不可逆髓过氧化物酶抑制剂。AZD3241的假想作用机制包括减少氧化应激，从而减少持续的神经炎症。这项2a期随机安慰剂对照多中心正电子发射断层扫描研究的目的是观察AZD3241治疗8周对帕金森病患者小胶质细胞的影响。帕金森患者每天两次口服AZD3241 600 mg或安慰剂(比例为3：1)，疗程为8周。分别在基线、4周和8周用正电子发射断层扫描检测C-11-PBR28与小胶质细胞标志18 kDa转位蛋白的结合。结果测量是总的分布量，用侵入性Logan图形分析估计。初步统计分析检查了与基线相比，AZD3241治疗后总分布量的变化。对AZD3241的安全性和耐受性的评估包括不良事件、生命体征、心电图和实验室测试的记录。这些患者的平均年龄为62岁(标准差=6岁)；男性21人，女性3人，平均帕金森氏病分级量表III评分(运动检查)范围为6至29分。在AD3241治疗组(n=18)，与转位蛋白结合的C-11-PBR28总分布量在第4周和第8周均较基线显著减少(P<；0.05)。8周时黑质纹状体区的分布体积减少13-16%，影响大小为0.5-0.6。安慰剂组(n=6)的总分布量没有总体变化。AZD3241是安全的，耐受性良好。帕金森病患者经AZD3241治疗后，脑内C-11-PBR28与转位蛋白结合减少，支持髓过氧化物酶抑制对小胶质细胞有影响的假说。本研究结果为AZD3241作用机制的证明提供了支持，并为进一步研究AZD3241治疗神经退行性疾病的疗效提供了依据。
Oxidative stress is implicated in neurodegeneration in Parkinson's disease. Jucaite et al. show that AZD3241 - an inhibitor of the reactive oxygen-generating enzyme myeloperoxidase - reduces binding of the PET ligand [C-11]PBR28 to a microglial marker translocator protein in patients. Myeloperoxidase inhibition may have the potential to reduce neuroinflammation and slow disease progression.Oxidative stress is implicated in neurodegeneration in Parkinson's disease. Jucaite et al. show that AZD3241 - an inhibitor of the reactive oxygen-generating enzyme myeloperoxidase - reduces binding of the PET ligand [C-11]PBR28 to a microglial marker translocator protein in patients. Myeloperoxidase inhibition may have the potential to reduce neuroinflammation and slow disease progression.Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of C-11-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of C-11-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of C-11-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.