中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (4): 898-904.doi: 10.4103/1673-5374.323077

• 原著:退行性病与再生 • 上一篇    下一篇

帕金森病NLRP3炎性小体活化的机制

  

  • 出版日期:2022-04-15 发布日期:2021-10-18

The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson’s disease

Jing Wang1, #, Xiao-Na Zhang1, #, Jin-Ni Fang1, Fei-Fei Hua1, Jing-Yang Han1, Zeng-Qiang Yuan2, An-Mu Xie1, *   

  1. 1Department of Neurology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 2Brain Science Center, Academy of Military Medical Sciences of PLA, Beijing, China
  • Online:2022-04-15 Published:2021-10-18
  • Contact: An-Mu Xie, PhD, xieanmu@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81971192 (to AMX).

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摘要：

既往研究发现，ATP–P2X4受体信号传导通路可介导NLRP3炎性小体的活化，而炎性小体又可能在糖尿病肾病中促进肾间质炎症的发生。由于炎症也在帕金森病的发生中起重要的作用，因此实验假设ATP–P2X4受体信号传导通路可能参与帕金森病中NLRP3炎性小体的激活。实验以黑质致密部立体定向注射6-羟基多巴胺建立了帕金森病雄性大鼠模型，发现其P2X4受体和NLRP3炎性小体成分（白细胞介素1β和白细胞介素18）被激活。而侧脑室注射选择性P2X4受体拮抗剂5-BDBD或以siRNA敲低P2X4受体表达则可抑制NLRP3炎性小体的活化，并减轻多巴胺能神经变性和神经炎症反应。提示ATP–P2X4受体信号传导通路能介导NLRP3炎性小体的活化，调节胶质细胞的激活、多巴胺能神经变性、铁代谢以及α-突触核蛋白和多巴胺的水平。这些发现揭示了ATP–P2X4轴在帕金森病发生中新的作用，从而为帕金森病的治疗提供新的靶点。实验于2015年3月5日经青岛大学动物伦理委员会批准（批准号QYFYWZLL 26119）。该研究已于2015年3月5日获得中国青岛大学动物伦理委员会批准（批准号QYFYWZLL 26119）。

https://orcid.org/0000-0003-2591-467X (An-Mu Xie)

关键词: 帕金森病, ATP-P2X4, NLRP3, 神经炎症, 神经退行性疾病, 氧化应激, 神经炎症反应, 铁代谢

Abstract: Previous studies have shown that the ATP-P2X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3 (NLRP3) inflammasome. The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy. As inflammation also plays an important role in the pathogenesis of Parkinson’s disease, we hypothesized that the ATP-P2X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson’s disease. A male rat model of Parkinson’s disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra. The P2X4 receptor and the NLRP3 inflammasome (interleukin-1β and interleukin-18) were activated. Intracerebroventricular injection of the selective P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) or knockdown of P2X4 receptor expression by siRNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation. Our results suggest that the ATP-P2X4 receptor signaling pathway mediates NLRP3 inflammasome activation, dopaminergic neurodegeneration, and dopamine levels. These findings reveal a novel role of the ATP-P2X4 axis in the molecular mechanisms underlying Parkinson’s disease, thus providing a new target for treatment. This study was approved by the Animal Ethics Committee of Qingdao University, China, on March 5, 2015 (approval No. QYFYWZLL 26119).

Key words: ATP, neurodegenerative disorder, neuroinflammation, neuroinflammatory response, NLRP3, P2X4, Parkinson’s disease

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