Outeiro Tiago Fleming, Grammatopoulos Tom N, Altmann Steven, Amore Allison, Standaert David G, Hyman Bradley T, Kazantsev Aleksey G
Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg. 114-3300, 16th St., Charlestown, MA 02129-4404, USA.
Biochem Biophys Res Commun. 2007 Jun 8;357(3):596-602. doi: 10.1016/j.bbrc.2007.03.163. Epub 2007 Apr 5.
Treatments based on pharmacological inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) have been suggested for a broad variety of human disorders, including Parkinson's disease (PD). The neuroprotective effects underlying the efficacy of PARP-1 inhibitors in PD models suggest a role for PARP-1 in neurodegeneration. In this study, we assessed the efficacy of PARP-1 inhibition in two distinct PD models. First, we tested a panel of small molecule PARP-1 inhibitors in alpha-synuclein (aSyn) cytotoxicity assay, where we observed compound-dependent ameliorating effects. Next, we tested the same panel in primary ventral mesencephalic neuronal cultures, treated with MPP(+). Dopaminergic neurons, the primary cells affected in PD, were selected and subjected to analysis. A significant ameliorating effect was achieved only with a highly potent PARP-1 inhibitor. Our data implicates aberrant PARP-1 function in different pathways of neurodegeneration. Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients.
基于对聚（ADP - 核糖）聚合酶 -1（PARP -1）进行药理抑制的治疗方法已被提议用于包括帕金森病（PD）在内的多种人类疾病。PARP -1抑制剂在PD模型中的疗效所基于的神经保护作用表明PARP -1在神经退行性变中起作用。在本研究中，我们评估了PARP -1抑制在两种不同PD模型中的疗效。首先，我们在α-突触核蛋白（aSyn）细胞毒性试验中测试了一组小分子PARP -1抑制剂，在该试验中我们观察到了化合物依赖性的改善作用。接下来，我们在经1 - 甲基 -4 - 苯基吡啶离子（MPP(+)）处理的原代腹侧中脑神经元培养物中测试了同一组抑制剂。选择PD中受影响的主要细胞——多巴胺能神经元并进行分析。仅使用一种高效的PARP -1抑制剂才实现了显著的改善作用。我们的数据表明PARP -1功能异常参与了神经退行性变的不同途径。此外，我们的结果为开发高效、生物可利用、可穿透大脑的PARP -1抑制剂以给帕金森病患者带来治疗益处提供了理论依据。
