2. Academic Validation
  3. Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury

Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury

  • Neurobiol Dis. 2018 Sep;117:15-27. doi: 10.1016/j.nbd.2018.05.016.
Xin Xu 1,  Dongpei Yin 1,  Honglei Ren 2,  Weiwei Gao 3,  Fei Li 4,  Dongdong Sun 1,  Yingang Wu 1,  Shuai Zhou 1,  Li Lyu 5,  Mengchen Yang 1,  Jianhua Xiong 1,  Lulu Han 2,  Rongcai Jiang 6,  Jianning Zhang 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China.
  • 2 Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China.
  • 3 Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China; Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, Tianjin 300350, China.
  • 4 Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China; Department of Neurosurgery, Tianjin Baodi Hospital, 8 Guangchuan Road, Tianjin 301800, China.
  • 5 Department of Cardiovascular, Tianjin Children's Hospital, 238 Longyan Road, Tianjin 300074, China.
  • 6 Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 154 Anshan Road, Tianjin 300052, China. Electronic address: [email protected].
PMID: 29859317 DOI: 10.1016/j.nbd.2018.05.016
Abstract

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6 h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.

Keywords

Interleukin-1β; MCC950; Microglia; NLRP3 inflammasome; Neuroinflammation; Traumatic brain injury.

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