Fang Jie, She Jing, Lin Fang, Wu Jun-Chao, Han Rong, Sheng Rui, Wang Guanghui, Qin Zheng-Hong
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Department of Pharmacology and Laboratory of Molecular Pathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Front Pharmacol. 2022 Apr 6;13:889383. doi: 10.3389/fphar.2022.889383. eCollection 2022.
Neuroinflammation plays an important role in the pathogenesis of many central nervous system diseases. Here, we investigated the effect of an anti-cancer compound RRx-001 on neuroinflammation and its possible new applications. BV2 cells and primary microglia cells were used to evaluate the role of RRx-001 in LPS-induced microglial activation and inflammatory response . And, we found that the increase in the synthesis and release of cytokines and the up-regulation of pro-inflammatory factors in LPS-treated microglial cells were significantly reduced by RRx-001 pretreatment. As the most classical inflammatory pathways, NF-κB and MAPK signaling pathways were activated by LPS, but were inhibited by RRx-001. Transcription of NLRP3 was also reduced by RRx-001. In addition, LPS induced oxidative stress by increasing the expression of Nox mediated by transcription factors NF-κB and AP-1, while RRx-001 pretreatment ameliorated Nox-mediated oxidative stress. LPS-induced activation of TAK1, an upstream regulator of NF-κB and MAPK pathways, was significantly inhibited by RRx-001 pretreatment, whereas recruitment of MyD88 to TLR4 was not affected by RRx-001. LPS-primed BV2 condition medium induced injury of primary neurons, and this effect was inhibited by RRx-001. Furthermore, we established a neuroinflammatory mouse model by stereotactic injection of LPS into the substantia nigra pars compacta (SNpc), and RRx-001 dose-dependently reduced LPS-induced microglial activation and loss of TH + neurons in the midbrain. In conclusion, the current study found that RRx-001 suppressed microglia activation and neuroinflammation through targeting TAK1, and may be a candidate for the treatment of neuroinflammation-related brain diseases.
神经炎症在许多中枢神经系统疾病的发病机制中起重要作用。在此，我们研究了抗癌化合物RRx-001对神经炎症的影响及其可能的新应用。使用BV2细胞和原代小胶质细胞来评估RRx-001在脂多糖（LPS）诱导的小胶质细胞活化和炎症反应中的作用。并且，我们发现RRx-001预处理显著降低了LPS处理的小胶质细胞中细胞因子合成和释放的增加以及促炎因子的上调。作为最经典的炎症途径，NF-κB和MAPK信号通路被LPS激活，但被RRx-001抑制。RRx-001还降低了NLRP3的转录。此外，LPS通过增加由转录因子NF-κB和AP-1介导的Nox表达来诱导氧化应激，而RRx-001预处理改善了Nox介导的氧化应激。RRx-001预处理显著抑制了LPS诱导的TAK1活化，TAK1是NF-κB和MAPK通路的上游调节因子，而MyD88向TLR4的募集不受RRx-001影响。LPS预处理的BV2条件培养基诱导原代神经元损伤，而这种作用被RRx-001抑制。此外，我们通过立体定向向黑质致密部（SNpc）注射LPS建立了神经炎症小鼠模型，并且RRx-001剂量依赖性地降低了LPS诱导的中脑小胶质细胞活化和TH +神经元的丢失。总之，当前研究发现RRx-001通过靶向TAK1抑制小胶质细胞活化和神经炎症，并且可能是治疗神经炎症相关脑部疾病的候选药物。
