2. Academic Validation
  3. RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage

RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage

  • Exp Neurol. 2017 Sep;295:116-124. doi: 10.1016/j.expneurol.2017.06.003.
Keren Zhou 1,  Ligen Shi 1,  Zhen Wang 1,  Jingyi Zhou 1,  Anatol Manaenko 2,  Cesar Reis 3,  Sheng Chen 4,  Jianmin Zhang 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Brain research institute, Zhejiang University, Hangzhou, Zhejiang, China; Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
  • 3 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
  • 4 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Brain research institute, Zhejiang University, Hangzhou, Zhejiang, China; Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: saintchan@zju.edu.cn.
  • 5 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Brain research institute, Zhejiang University, Hangzhou, Zhejiang, China; Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: zjm135@zju.edu.cn.
PMID: 28579326 DOI: 10.1016/j.expneurol.2017.06.003
Abstract

The NLRP3 inflammasome functions as a crucial component of the inflammatory response in early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the activation of NLRP3 inflammasome has not been well elucidated. In this study, we hypothesized the RIP1-RIP3-DRP1 pathway was involved in the activation of the NLRP3 inflammasome following SAH. SAH was induced by endovascular perforation in rats. Necrostatin-1 (Nec-1) or mitochondrial division inhibitor (Mdivi-1) was administered 1h after SAH by intraperitoneal injection. SAH grade, neurological function, brain water content, Western blot, ROS assay, immunofluorescence and transmission electron microscopy were performed. SAH led to the upregulation of RIP1, RIP3, phosphorylated DRP1 and NLRP3 inflammasome. Nec-1 treatment reduced RIP1, RIP3, phosphorylated DRP1 and NLRP3 inflammasome, subsequently alleviated brain edema and neurological deficits at 24h following SAH. The treatment with Mdivi-1 inhibited the expression of DRP1 protein, attenuated mitochondria damage and the generation of ROS, inhibited NLRP3 inflammasome and ameliorated brain edema and neurological deficits at 24h after SAH. The activation of the NLRP3 inflammasome in EBI after SAH was mediated by RIP1-RIP3-DRP1 pathway. Nec-1 and Mdivi-1 can inhibit inflammation and improve neurological function after SAH.

Keywords

DRP1; Early brain injury; NLRP3; RIP1; RIP3; Subarachnoid hemorrhage.

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