Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy.

中文翻译：

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Olaparib，一种PARP-1抑制剂，在亨廷顿舞蹈病的R6 / 2小鼠模型中调节炎症小体和细胞凋亡

细胞凋亡是一种依赖caspase-1（Casp-1）的细胞死亡，导致细胞快速裂解，并且与炎症小体有关。我们最近发现，在亨廷顿舞蹈病（HD）中发生了焦细胞凋亡。此外，我们先前描述了PARP-1抑制剂对HD的有益作用。在这项研究中，我们研究了亨帕顿氏病小鼠模型中PARP-1抑制剂Olaparib的神经保护作用。从症状发生前到晚期，给奥拉帕比（Olapaparib）或媒介物施用R6 / 2小鼠。进行了行为研究以研究该化合物的临床效果。进行了免疫组织化学和蛋白质印迹研究，以评估HD小鼠的神经保护作用以及该化合物对神经元死亡途径的影响。我们的结果表明，从神经退行性疾病的症状发生前阶段开始服用Olaparib，主要是通过调节炎症小体的活化，从而提高了存活率，减轻了神经功能缺损并改善了神经行为学测试的临床效果。这些结果表明，已经用作抗肿瘤化合物的市售药物Olaparib发挥神经保护作用，并且可能是亨廷顿氏病治疗的有用药物。