School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China.
Amino Acids. 2018 May;50(5):547-556. doi: 10.1007/s00726-018-2547-1. Epub 2018 Mar 5.
Beyond nigrostriatal dopaminergic system, the noradrenergic locus coeruleus (LC/NE) neurons are also degenerated in patients with Parkinson's disease (PD), the second most common neurodegenerative disorder. We previously reported that microglia-mediated neuroinflammation contributes to LC/NE neurodegeneration. The purpose of this study is aimed to test whether taurine, an endogenous amino acid, could be able to protect LC/NE neurons through inhibition of microglial activation using paraquat and maneb-induced mouse PD model. Taurine (150 mg/kg) was administrated (i.p) to mice 30 min prior to paraquat (10 mg/kg) and maneb (30 mg/kg) intoxication for consecutive 6 weeks (twice per week). The results clearly demonstrated that paraquat and maneb co-exposure resulted in loss of tyrosine hydroxylase-positive neurons in the LC in mice, which was significantly ameliorated by taurine. Mechanistically, inhibition of microglia-mediated neuroinflammation contributed to taurine-afforded neuroprotection. Taurine attenuated paraquat and maneb-induced microglial activation and M1 polarization as well as release of proinflammatory cytokines in brainstem of mice. Taurine also abrogated microglial NADPH oxidase activation and oxidative damage in paraquat and maneb-treated mice. Furthermore, inhibition of nuclear factor-κB (NF-κB) but not signal transducers and activators of transcription 1/3 (STAT1/3) signaling pathway participated in taurine-inhibited microglial activation. Collectively, taurine exerted LC/NE neuroprotection against microglia-mediated neurotoxicity. The robust neuroprotective effects of taurine suggest that taurine may be a promising candidate for potential therapy for patients suffering from PD.
除了黑质纹状体多巴胺能系统，去甲肾上腺素能蓝斑核（LC/NE）神经元也在帕金森病（PD）患者中退化，PD 是第二常见的神经退行性疾病。我们之前报道过，小胶质细胞介导的神经炎症有助于 LC/NE 神经元变性。本研究旨在通过使用百草枯和代森锰诱导的 PD 小鼠模型，测试内源性氨基酸牛磺酸是否能够通过抑制小胶质细胞激活来保护 LC/NE 神经元。牛磺酸（150mg/kg）在百草枯（10mg/kg）和代森锰（30mg/kg）中毒前 30 分钟（i.p）给予小鼠，连续 6 周（每周两次）。结果清楚地表明，百草枯和代森锰共同暴露导致 LC 中酪氨酸羟化酶阳性神经元丧失，牛磺酸显著改善了这一现象。从机制上讲，抑制小胶质细胞介导的神经炎症有助于牛磺酸提供神经保护。牛磺酸减弱了百草枯和代森锰诱导的小鼠脑干中小胶质细胞的激活和 M1 极化以及促炎细胞因子的释放。牛磺酸还消除了百草枯和代森锰处理小鼠中小胶质细胞 NADPH 氧化酶的激活和氧化损伤。此外，核因子-κB（NF-κB）而非信号转导和转录激活因子 1/3（STAT1/3）信号通路的抑制参与了牛磺酸抑制小胶质细胞激活。总之，牛磺酸对 LC/NE 神经元发挥了神经保护作用，对抗小胶质细胞介导的神经毒性。牛磺酸具有强大的神经保护作用，表明牛磺酸可能是治疗 PD 患者的有前途的候选药物。
