POLYDATIN AMELIORATES TRAUMATIC BRAIN INJURY-INDUCED SECONDARY BRAIN INJURY BY INHIBITING NLRP3-INDUCED NEUROINFLAMMATION ASSOCIATED WITH SOD2 ACETYLATION
POLYDATIN AMELIORATES TRAUMATIC BRAIN INJURY-INDUCED SECONDARY BRAIN INJURY BY INHIBITING NLRP3-INDUCED NEUROINFLAMMATION ASSOCIATED WITH SOD2 ACETYLATION
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虎杖甙通过抑制 NLRP3 诱导的与 SOD2 乙酰化相关的神经炎症来改善创伤性脑损伤 - 引起的继发性脑损伤
DOI：
10.1097/shk.0000000000002066
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发表时间：
2023-03-01
期刊：
影响因子：
3.1
通讯作者：
Li，Li
中科院分区：
文献类型：
--
作者：
Li，Qin;Zhao，Peng;Li，Li
摘要颅脑损伤是一种发病率高、死亡率高、致残率高的疾病，其发病机制尚不清楚。研究表明，神经元和星形胶质细胞中核苷酸结合的寡聚化结构域样受体3(NLRP3)的激活参与了脑创伤后的神经炎性级联反应。更重要的是，虎杖苷(PD)已被证明对脑损伤诱导的神经炎症有保护作用，但其机制尚不清楚。推测PD可能通过超氧化物歧化酶(SOD2)-NLRP3信号通路减轻脑损伤后神经炎性损伤，SOD2可能参与调节NLRP3炎症体的激活。建立了模拟颅脑损伤的体内侧向液压冲击损伤模型和体外细胞拉伸损伤模型。伤后即刻给予NLRP3化学抑制剂MCC950、SOD2抑制剂2-甲氧基雌二醇和PD。结果表明，创伤后PC12细胞SOD2乙酰化(SOD2 Ac-K122)、NLRP3和裂解caspase-1的表达均显著增加，而SOD2抑制剂2-甲氧基雌二醇显著促进SOD2 Ac-K122、NLRP3和裂解caspase-1的表达，并加重线粒体氧自由基(MtROS)积聚和线粒体膜电位(MMPs)的崩溃。而NLRP3抑制剂MCC950在体内外均能显著抑制脑损伤后caspase-1的激活，同时，MCC950还能抑制脑损伤后mtROS积聚和线粒体膜基质崩解。更重要的是，PD在体内和体外均能抑制脑损伤后SOD2Ac-K122、NLRP3和caspase-1的表达，促进SOD2的表达。虎杖苷还能抑制牵张损伤后mtROS的积聚和线粒体膜的崩解。提示PD可抑制SOD2乙酰化，从而减轻NLRP3炎性小体的激活，从而对脑损伤的神经炎症起到保护作用。
ABSTRACT Traumatic brain injury (TBI) is a kind of disease with high morbidity, mortality, and disability, and its pathogenesis is still unclear. Research shows that nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) activation in neurons and astrocytes is involved in neuroinflammatory cascades after TBI. What is more, polydatin (PD) has been shown to have a protective effect on TBI-induced neuroinflammation, but the mechanisms remain unclear. Here, we speculated that PD could alleviate TBI-induced neuroinflammatory damage through the superoxide dismutase (SOD2)-NLRP3 signal pathway, and SOD2 might regulate NLRP3 inflammasome activation. The model of lateral fluid percussion for in vivo and cell stretching injury for in vitro were established to mimic TBI. NLRP3 chemical inhibitor MCC950, SOD2 inhibitor 2-methoxyestradiol, and PD were administered immediately after TBI. As a result, the expression of SOD2 acetylation (SOD2 Ac-K122), NLRP3, and cleaved caspase-1 were increased after TBI both in vivo and in vitro, and using SOD2 inhibitor 2-methoxyestradiol significantly promoted SOD2 Ac-K122, NLRP3, and cleaved caspase-1 expression, as well as exacerbated mitochondrial ROS (mtROS) accumulation and mitochondrial membrane potential (MMP) collapse in PC12 cells. However, using NLRP3 inhibitor MCC950 significantly inhibited cleaved caspase-1 activation after TBI both in vivo and in vitro; meanwhile, MCC950 inhibited mtROS accumulation and MMP collapse after TBI. More importantly, PD could inhibit the level of SOD2 Ac-K122, NLRP3, and cleaved caspase-1 and promote the expression of SOD2 after TBI both in vivo and in vitro. Polydatin also inhibited mtROS accumulation and MMP collapse after stretching injury. These results indicated that PD inhibited SOD2 acetylation to alleviate NLRP3 inflammasome activation, thus acting a protective role against TBI neuroinflammation.