Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.
Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
Biochem Biophys Res Commun. 2021 Feb 12;540:22-28. doi: 10.1016/j.bbrc.2020.12.097. Epub 2021 Jan 9.
Mounting evidence has implicated inflammation in ischemia-reperfusion injury following acute ischemic stroke (AIS). Microglia remain the primary initiator and participant of brain inflammation. Emerging evidence has indicated that uric acid has promise for the treatment of AIS, but its explicit mechanisms remain elusive. Here, we observed that uric acid reduced the severity of cerebral infarction and attenuated the activation of microglia in the cerebral cortex in a mouse middle cerebral-artery occlusion/reperfusion model. Thus, we speculated that uric acid may play a role by directly interfering with the inflammatory response of microglia. First, we investigated whether the HMGB1-TLR4-NF-κB signaling plays a role in oxygen glucose deprivation and reperfusion (OGD/R) injury of BV2 cells. Inhibition of the signaling significantly reduced the release of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL1β), and IL6 caused by OGD/R in BV2 cells. Second, uric acid weakened the decreased cell viability and lactate dehydrogenase release induced by OGD/R in BV2 cells. Finally, uric acid reduced the release of the proinflammatory cytokines TNF-α, IL1β, and IL6 caused by OGD/R in BV2 cells by dampening HMGB1-TLR4-NF-κB signaling, which was reversed by probenecid treatment, an inhibitor of the uric acid channel. Hence, uric acid halted the release of inflammatory factors and the decreased cell viability induced by ODG/R via inhibiting the microglia HMGB1-TLR4-NF-κB signaling, thereby alleviating the damage to microglia. This may be part of the molecular mechanisms by which uric acid protects mice against the brain damage of middle cerebral-artery occlusion/reperfusion.
越来越多的证据表明，炎症参与了急性缺血性脑卒中（AIS）后的缺血再灌注损伤。小胶质细胞仍然是脑内炎症的主要启动者和参与者。新出现的证据表明，尿酸有望用于治疗 AIS，但具体机制仍不清楚。在这里，我们观察到尿酸可减轻大脑中动脉闭塞/再灌注模型中小鼠脑梗死的严重程度，并减弱大脑皮层中小胶质细胞的激活。因此，我们推测尿酸可能通过直接干扰小胶质细胞的炎症反应发挥作用。首先，我们研究了高迁移率族蛋白 1（HMGB1）-Toll 样受体 4（TLR4）-核因子-κB（NF-κB）信号通路是否在氧葡萄糖剥夺和再灌注（OGD/R）损伤 BV2 细胞中发挥作用。抑制该信号通路可显著减少 OGD/R 引起的 BV2 细胞中促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素 1β（IL1β）和白细胞介素 6（IL6）的释放。其次，尿酸减弱了 OGD/R 诱导的 BV2 细胞活力降低和乳酸脱氢酶释放。最后，尿酸通过抑制 HMGB1-TLR4-NF-κB 信号通路减少了由 OGD/R 引起的 BV2 细胞中促炎细胞因子 TNF-α、IL1β 和 IL6 的释放，该作用可被尿酸通道抑制剂丙磺舒所逆转。因此，尿酸通过抑制小胶质细胞的 HMGB1-TLR4-NF-κB 信号通路，阻止 ODG/R 诱导的炎症因子释放和细胞活力降低，从而减轻小胶质细胞的损伤。这可能是尿酸保护小鼠免受大脑中动脉闭塞/再灌注损伤的部分分子机制。
