Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.
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.
Xu X
，Yin D
，Ren H
，Gao W
，Li F
，Sun D
，Wu Y
，Zhou S
，Lyu L
，Yang M
，Xiong J
，Han L
，Jiang R
，Zhang J
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MCC950 attenuated early brain injury by suppressing NLRP3 inflammasome after experimental SAH in rats.
Nucleotide oligomerization domain(NOD)-like receptor protein-3(NLRP3) inflammasome is a multiprotein complex, which results in the inflammatory response in early brain injury(EBI) after subarachnoid hemorrhage(SAH). MCC950, a specific NLRP3 inhibitor, plays neuroprotective effects in several central nervous system diseases. However, the role of MCC950 in SAH remains elusive. This study aims to investigate whether MCC950 exerts neuroprotection after experimental SAH and further explore the potential mechanisms. The SAH model was induced by endovascular perforation process using adult male Sprague-Dawley rats. MCC950 was injected intraperitoneally 1 h after SAH with a dose of 10 mg/kg. The results showed that MCC950 significantly ameliorated severe brain edema and neurological dysfunction. Furthermore, MCC950 efficiently reduced NLRP3 inflammasome expression as well as the pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. In addition, the protective effect of MCC950 was blunted by lipopolysaccharide. In conclusion, our findings suggest that MCC950 alleviated SAH-induced EBI by suppressing inflammation.
Luo Y
，Lu J
，Ruan W
，Guo X
，Chen S
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A selective NLRP3 inflammasome inhibitor attenuates behavioral deficits and neuroinflammation in a mouse model of Parkinson's disease.
Nod-like receptor pyrin containing (NLRP)3 inflammasome-mediated neuroinflammation is involved in the pathology of Parkinson's disease (PD), but the roles of other inflammasomes in PD remain unclear. The NLRP3 inhibitor MCC950 exerts neuroprotective effects in several neurological diseases. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model with or without intraperitoneal MCC950 administration, we assessed whether specifically the NLRP3 inflammasome is activated in the nigrostriatal system and whether MCC950 has therapeutic potential in this PD model. Western blots were used to determine the nigrostriatal expression of inflammasome-specific proteins, including NLRP1, NLRP2, NLRP3, nod-like receptor CARD containing 4 (NLRC4), and absent in melanoma 2 (AIM2). The pole, hanging, and swimming tests were used to assess functional deficits, western blots and immunostainings were used to analyze dopaminergic neuronal degeneration, as well as activation of glial cells and the NLRP3 inflammasome. NLRP3 expression in the nigrostriatal system of MPTP-induced mice was significantly increased compared to control, whereas NLRP1, NLRP2, NLRC4, and AIM2 expression in the nigrostriatal system, as well as NLRP3 expression in the cerebral cortex and hippocampus, were similar in the two groups. Furthermore, MPTP-induced mice exhibited behavioral dysfunctions, dopaminergic neuronal degeneration, and activation of glial cells and the NLRP3 inflammasome. MCC950 treatment of MPTP-induced mice improved behavioral dysfunctions, reduced dopaminergic neuronal degeneration, and inhibited the activation of glial cells and the NLRP3 inflammasome. In conclusion, these findings indicated that NLRP3, not NLRP1, NLRP2, NLRC4, and AIM2, may be the key inflammasome that promotes MPTP-induced pathogenesis. MCC950 protects against MPTP-induced nigrostriatal damage and may be a novel promising therapeutic approach in treating MPTP-induced PD.
Huang S
，Chen Z
，Fan B
，Chen Y
，Zhou L
，Jiang B
，Long H
，Zhong W
，Li X
，Li Y
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