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Melatonin ameliorates Parkinson’s disease via regulating microglia polarization in a RORα‐dependent pathway
npj Parkinson's Disease ( IF 6.7 ) Pub Date : 2022-07-08 , DOI: 10.1038/s41531-022-00352-5
Jingwen Li 1 , Hanshu Liu 1 , Xinyi Wang 1 , Yun Xia 1 , Jinsha Huang 1 , Tao Wang 1 , Zhicheng Lin 2 , Nian Xiong 1
Affiliation  

An important pathophysiological component of Parkinson’s Disease (PD) is circadian rhythm disorder, closely related to a decrease in circulated melatonin (MLT) level. It has been reported recently that retinoic acid-associated orphan nuclear receptor (RORα), for the potentiallyendogenous ligand MLT, plays an important role in various diseases. However, the function of RORα in the pathogenesis of neurodegenerative diseases remains much unclear. Here, we showed in a cellular PD model that RORα expression was down-regulated in 1 methyl 4 phenyl pyridinium ion (MPP+)-treated BV2 cells but up-regulated by MLT. Of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - induced mouse model with RORα levels reduced in the midbrain tissue, MLT treatment (intraperitoneal 20 mg/kg/d for 7 days) significantly increased the RORα levels and protected dopamine neurons, with decreased inflammation and increased anti-inflammatory M2-like phenotype in the microglia. Furthermore, siRNA-mediated knockdown implied the involvement of signal transducer and activator of transcription (STAT) pathway. In conclusion, MLT ameliorates neuroinflammation by inhibiting STAT-related pro-inflammatory (M1-like) polarization of microglia, revealing alternative options for neuroprotective treatment of PD.



中文翻译:

褪黑激素通过调节 RORα 依赖途径中的小胶质细胞极化来改善帕金森病

帕金森病 (PD) 的一个重要病理生理成分是昼夜节律紊乱,与循环褪黑激素 (MLT) 水平的降低密切相关。最近有报道称,视黄酸相关孤儿核受体(RORα)作为潜在的内源性配体 MLT,在各种疾病中起重要作用。然而,RORα在神经退行性疾病发病机制中的作用仍不清楚。在这里,我们在细胞 PD 模型中显示,RORα 表达在 1 甲基 4 苯基吡啶鎓离子(MPP +) 处理的 BV2 细胞,但被 MLT 上调。在中脑组织中 RORα 水平降低的 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的小鼠模型中,MLT 治疗(腹膜内 20 mg/kg/d 7 天)显着增加 RORα 水平并保护多巴胺神经元,减少炎症和增加小胶质细胞中的抗炎 M2 样表型。此外,siRNA 介导的敲低暗示信号转导和转录激活因子 (STAT) 通路的参与。总之,MLT 通过抑制小胶质细胞的 STAT 相关促炎(M1 样)极化来改善神经炎症,揭示了 PD 神经保护治疗的替代选择。

更新日期:2022-07-08
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