5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells aga
5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells aga
复制标题
5-(3,4-二氟苯基)-3-(6-甲基吡啶-3-基)-1,2,4-恶二唑 (DDO-7263) 是一种针对脑组织的新型 Nrf2 激活剂，可预防 MPTP 诱导的亚急性帕金森病
DOI：
10.1016/j.freeradbiomed.2019.01.003
复制
发表时间：
2019
影响因子：
7.4
通讯作者：
Di Bin
中科院分区：
文献类型：
--
作者：
Xu Li Li;Wu Yu Feng;Yan Fang;Li Cui Cui;Dai Zhen;You Qi Dong;Jiang Zheng Yu;Di Bin
帕金森病(PD)是全球第二常见的与衰老相关的神经退行性疾病。氧化应激和神经炎症是帕金森病多巴胺能神经元变性的关键事件。本研究发现，我们报道的新型Nrf2-ARE激活剂ddo -7263对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠帕金森病具有理想的治疗效果。ddo -7263改善MPTP诱导小鼠行为异常，显著减轻小鼠脑黑质（SN）和纹状体化学诱导的多巴胺能神经元酪氨酸羟化酶（TH）缺失，抑制炎症因子分泌。此外，ddo -7263还能保护PC12神经元免受h2o2诱导的氧化损伤。体外和体内模型均证实了ddo -7263的神经保护作用。进一步研究表明，ddo -7263的神经保护作用是通过激活Nrf2-ARE信号通路和抑制NLRP3炎性小体激活介导的。ddo -7263诱导的NLRP3炎性体抑制依赖于Nrf2的激活。这一结论在thp -1来源的巨噬细胞（THP-Ms）中也得到了证实。在atp - lps暴露的THP-Ms细胞中，ddo -7263显著抑制NLRP3的激活、裂解caspase-1的产生和IL-1β蛋白的表达。药动学参数和组织分布结果表明，ddo -7263具有脑组织靶向功能。这些证据表明，ddo -7263对PD等神经退行性疾病具有理想的治疗效果。
Parkinson's disease (PD) is the second most common aging-related neurodegenerative disease worldwide. Oxidative stress and neuroinflammation are critical events in the degeneration of dopaminergic neurons in PD. In this study, we found thatDDO-7263, a novel Nrf2-ARE activator reported by us, has ideal therapeutic effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice.DDO-7263improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatum of the mouse brain and inhibited the secretion of inflammatory factors. In addition,DDO-7263protected PC12 neurons from H2O2-induced oxidative damage. The neuroprotective effects ofDDO-7263were confirmed both in vitro and in vivo models. Further studies showed that the neuroprotective effect ofDDO-7263was mediated by the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation.DDO-7263induced NLRP3 inflammasome inhibition is dependent on Nrf2 activation. This conclusion was also verified in THP-1-derived macrophages (THP-Ms).DDO-7263significantly inhibited NLRP3 activation, cleaved caspase-1 production and IL-1β protein expression in ATP-LPS-exposed THP-Ms cells. The pharmacokinetic parameters and tissue distribution results indicated thatDDO-7263has a brain tissue targeting function. All these lines of evidence show thatDDO-7263has ideal therapeutic effects on neurodegenerative diseases such as PD.