Objective To investigate the protective effects of MCC950 on traumatic brain injury (TBI) mice by inhibiting pyroptosis via suppressing NLRP3 inflammasome. Methods A total of 36 BALB/c mice were randomly divided into the following groups: a sham injury group, a TBI model group, a MCC950 1-day and 7-day treatment group. The TBI model of mice was induced by free fall method, and MCC950 was intraperitoneally injected into the treatment group after modeling. HE staining and nissl staining were used to evaluate the brain tissue injury conditions of each group. The expressions of NLRP3, Caspase1 and GSDMD in each group were detected by the immunofluorescence. Results H&E staining showed that compared with the sham injury group, the number of neurons in the injured area in the TBI model group decreased, and the nuclei of neurons were consolidated and hyperchromatic, with a large number of vacuoles around the nuclei. The neuron status of the TBI+MCC950 treatment group (1-day and 7-day treatment group) were significantly better than that of the TBI model group. Nissl staining showed that compared with the TBI model group, the neuron loss and injury in the TBI+MCC950 treatment group (1-day and 7-day treatment group) attenuated. Immunofluorescence showed that compared with the TBI model group, the expression levels of NLRP3, caspase1 and GSDMD in frozen sections of brain tissues of the TBI+MCC950 group (1-day and 7-day treatment group) significantly reduced. Conclusions Application of MCC950 in the treatment of TBI mice can effectively inhibit NLRP3-mediated pyroptosis and alleviate the damage of brain tissue and cell structure at the wound site.
ZHUANG Jian, LUO Xiao-qing, WU Shu-fan, HE Yi, LI Jie
. Protective effects of inhibiting NLRP3 mediated pyroptosis on traumatic brain injury mice[J]. Chinese Journal of Clinical Anatomy, 2020
, 38(4)
: 428
-433
.
DOI: 10.13418/j.issn.1001-165x.2020.04.012
[1] Pang AL, Xiong LL, Xia QJ, et al. Neural stem cell transplantation is associated with inhibition of apoptosis, Bcl-xL upregulation, and recovery of neurological function in a rat model of traumatic brain injury[J]. Cell Transplant, 2017, 26(7): 1262-1275.
[2] Feigin VL, Theadom A, Barker-Collo S, et al. Incidence of traumatic brain injury in New Zealand: a population-based study[J]. Lancet Neurol, 2013, 12(1): 53-64.
[3] Liu YW, Li S, Dai SS. Neutrophils in traumatic brain injury (TBI): friend or foe[J]? J Neuroinflammation, 2018, 15(1): 146.
[4] Helmy A, Carpenter KL, Menon DK, et al. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production[J]. J Cereb Blood Flow Metab, 2011, 31(2): 658-670.
[5] 黄清宇, 杜楚江, 张雨竹, 等. 细胞焦亡研究进展[J]. 中国免疫学杂志, 2020, 36(2): 245-250.
[6] 杨婷, 姚丽芬. 细胞焦亡: 中枢神经系统的一种可能新型靶向干预[J]. 脑与神经疾病杂志, 2017, 25(4): 249-252.
[7] Eren E, özören N. The NLRP3 inflammasome: a new player in neurological diseases[J]. Turk J Biol, 2019, 43(6): 349-359.
[8] Dempsey C, Rubio AA, Bryson KJ, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice[J]. Brain Behav Immun, 2017, 61: 306-316.
[9] Yang Y, Wang H, Kouadir M, et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors[J]. Cell Death Dis, 2019, 10(2): 128.
[10] Shao BZ, Xu ZQ, Han BZ, et al. NLRP3 inflammasome and its inhibitors: a review[J]. Front Pharmacol, 2015, 6: 262.
[11] Coll RC, Hill JR, Day CJ, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition[J]. Nat Chem Biol, 2019, 15(6): 556-559.
[12] Flierl MA, Stahel PF, Beauchamp KM, et al. Mouse closed head injury model induced by a weight-drop device[J]. Nat Protoc, 2009, 4(9): 1328-1337.
[13] Shi JJ, Gao WQ, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death[J]. Trends Biochem Sci, 2017, 42(4): 245-254.
[14] Kuwar R, Rolfe A, Di L, et al. A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury[J]. J Neuroinflammation, 2019, 16(1): 81.
[15] O'Brien WT, Pham L, Symons GF, et al. The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and the rapeutic target[J]. J Neuroinflammation, 2020, 17(1): 104.
