School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China.
State Key Laboratory of Natural Products and Functions, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
Cell Death Dis. 2018 Apr 1;9(4):435. doi: 10.1038/s41419-018-0468-2.
Microglia-mediated neuroinflammation is implicated in multiple neurodegenerative disorders, including Parkinson's disease (PD). Hence, the modulatioein of sustained microglial activation may have therapeutic potential. This study is designed to test the neuroprotective efficacy of taurine, a major intracellular free β-amino acid in mammalian tissues, by using paraquat and maneb-induced PD model. Results showed that mice intoxicated with paraquat and maneb displayed progressive dopaminergic neurodegeneration and motor deficits, which was significantly ameliorated by taurine. Taurine also attenuated the aggregation of α-synuclein in paraquat and maneb-intoxicated mice. Mechanistically, taurine suppressed paraquat and maneb-induced microglial activation. Moreover, depletion of microglia abrogated the dopaminergic neuroprotective effects of taurine, revealing the role of microglial activation in taurine-afforded neuroprotection. Subsequently, we found that taurine suppressed paraquat and maneb-induced microglial M1 polarization and gene expression levels of proinflammatory factors. Furthermore, taurine was shown to be able to inhibit the activation of NADPH oxidase (NOX2) by interfering with membrane translocation of cytosolic subunit, p47 and nuclear factor-kappa B (NF-κB) pathway, two key factors for the initiation and maintenance of M1 microglial inflammatory response. Altogether, our results showed that taurine exerted dopaminergic neuroprotection through inactivation of microglia-mediated neuroinflammation, providing a promising avenue and candidate for the potential therapy for patients suffering from PD.
小胶质细胞介导的神经炎症与多种神经退行性疾病有关，包括帕金森病（PD）。因此，调节持续的小胶质细胞激活可能具有治疗潜力。本研究旨在通过使用百草枯和代森锰诱导的 PD 模型来测试牛磺酸（哺乳动物组织中主要的细胞内游离β-氨基酸）的神经保护功效。结果表明，百草枯和代森锰中毒的小鼠表现出进行性多巴胺能神经退行性变和运动功能障碍，牛磺酸可显著改善这些症状。牛磺酸还减轻了百草枯和代森锰中毒小鼠中α-突触核蛋白的聚集。在机制上，牛磺酸抑制了百草枯和代森锰诱导的小胶质细胞激活。此外，小胶质细胞耗竭消除了牛磺酸对多巴胺能神经的保护作用，表明小胶质细胞激活在牛磺酸提供的神经保护中起作用。随后，我们发现牛磺酸抑制了百草枯和代森锰诱导的小胶质细胞 M1 极化和促炎因子的基因表达水平。此外，牛磺酸通过干扰细胞溶质亚基 p47 和核因子-κB（NF-κB）途径的膜易位，能够抑制 NADPH 氧化酶（NOX2）的激活，这两个因素对于 M1 小胶质细胞炎症反应的启动和维持至关重要。总之，我们的结果表明，牛磺酸通过抑制小胶质细胞介导的神经炎症发挥多巴胺能神经保护作用，为治疗 PD 患者提供了有前途的途径和候选药物。
