Bao Bing, Yin Xiao-Ping, Wen Xiao-Qing, Suo Yi-Jun, Chen Zhi-Ying, Li Dong-Ling, Lai Qin, Cao Xian-Ming, Qu Qiu-Min
Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Department of Neurology, The Affiliated Hospital of Jiujiang University, No.57 Xunyang East Rode, Xunyang District, Jiujiang, 332000, China.
Department of Neurology, The Affiliated Hospital of Jiujiang University, No.57 Xunyang East Rode, Xunyang District, Jiujiang, 332000, China.
Neurochem Int. 2023 Nov;170:105603. doi: 10.1016/j.neuint.2023.105603. Epub 2023 Aug 25.
Intracerebral hemorrhage (ICH), which has high mortality and disability rate is associated with microglial pyroptosis and neuroinflammation, and the effective treatment methods are limited Epigallocatechin-3-gallate (EGCG) has been found to play a cytoprotective role by regulating the anti-inflammatory response to pyroptosis in other systemic diseases. However, the role of EGCG in microglial pyroptosis and neuroinflammation after ICH remains unclear. In this study, we investigated the effects of EGCG pretreatment on neuroinflammation-mediated neuronal pyroptosis and the underlying neuroprotective mechanisms in experimental ICH. EGCG pretreatment was found to remarkably improved neurobehavioral performance, and decreased the hematoma volume and cerebral edema in mice. We found that EGCG pretreatment attenuated the release of hemin-induced inflammatory cytokines (IL-1β, IL-18, and TNF-α). EGCG significantly upregulated the expression of heme oxygenase-1 (HO-1), and downregulated the levels of pyroptotic molecules and inflammatory cytokines including Caspase-1, GSDMD, NLRP3, mature IL-1β, and IL-18. EGCG pretreatment also decreased the number of Caspase-1-positive microglia and GSDMD along with NLRP3-positive microglia after ICH. Conversely, an HO-1-specific inhibitor (ZnPP), significantly inhibited the anti-pyroptosis and anti-neuroinflammation effects of EGCG. Therefore, EGCG pretreatment alleviated microglial pyroptosis and neuroinflammation, at least in part through the Caspase-1/GSDMD/NLRP3 pathway by upregulating HO-1 expression after ICH. In addition, EGCG pretreatment promoted the polarization of microglia from the M1 phenotype to M2 phenotype after ICH. The results suggest that EGCG is a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.
脑出血（ICH）具有高死亡率和致残率，与小胶质细胞焦亡和神经炎症相关，且有效治疗方法有限。表没食子儿茶素没食子酸酯（EGCG）已被发现在其他全身性疾病中通过调节对焦亡的抗炎反应发挥细胞保护作用。然而，EGCG在脑出血后小胶质细胞焦亡和神经炎症中的作用仍不清楚。在本研究中，我们调查了EGCG预处理对实验性脑出血中神经炎症介导的神经元焦亡的影响及其潜在的神经保护机制。发现EGCG预处理可显著改善小鼠的神经行为表现，并减少血肿体积和脑水肿。我们发现EGCG预处理可减轻血红素诱导的炎性细胞因子（IL-1β、IL-18和TNF-α）的释放。EGCG显著上调血红素加氧酶-1（HO-1）的表达，并下调包括半胱天冬酶-1、Gasdermin D（GSDMD）、NLR家族含pyrin结构域蛋白3（NLRP3）、成熟IL-1β和IL-18在内的焦亡分子和炎性细胞因子水平。EGCG预处理还可减少脑出血后半胱天冬酶-1阳性小胶质细胞以及GSDMD与NLRP3阳性小胶质细胞的数量。相反，一种HO-1特异性抑制剂（ZnPP）显著抑制了EGCG的抗焦亡和抗神经炎症作用。因此，EGCG预处理至少部分通过上调脑出血后HO-1的表达，经由半胱天冬酶-1/GSDMD/NLRP3途径减轻小胶质细胞焦亡和神经炎症。此外，EGCG预处理促进脑出血后小胶质细胞从M1表型向M2表型极化。结果表明，EGCG是一种通过脑出血后抗焦亡作用减轻神经炎症的潜在药物。
