Hepatic ischemia-reperfusion (HIR) has been proven to trigger oxidative stress and pyroptosis in the hippocampus. Sirtuin 3 (SIRT3) is an essential mitochondrial protein deacetylase regulating oxidative stress and mitophagy. Dexmedetomidine (Dex) has been demonstrated to confer neuroprotection in different brain injury models. However, whether the protective effects of Dex following HIR are orchestrated by activation of SIRT3-mediated mitophagy and inhibition of NOD-like receptor protein 3 (NLRP3) inflammasome activation remains unknown. Herein, two-week-old rats were treated with Dex or a selective SIRT3 inhibitor (3-TYP)/autophagy inhibitor (3-MA) and then subjected to HIR. The results revealed that Dex treatment effectively attenuated neuroinflammation and cognitive deficits via upregulating SIRT3 expression and activity. Furthermore, Dex treatment inhibited the activation of NLRP3 inflammasome, while 3-TYP and 3-MA eliminated the protective effects of Dex, suggesting that SIRT3-mediated mitophagy executes the protective effects of Dex. Moreover, 3-TYP treatment downregulated the expression level of SIRT3 downstream proteins: forkhead-box-protein 3α (FOXO3α), superoxide dismutase 2 (SOD2), peroxiredoxin 3 (PRDX3), and cyclophilin D (CYP-D), which were barely influenced by 3-MA treatment. Notably, both 3-TYP and 3-MA were able to offset the antioxidative and antiapoptosis effects of Dex, indicating that SIRT3-mediated mitophagy may be the last step and the major pathway executing the neuroprotective effects of Dex. In conclusion, Dex inhibits HIR-induced NLRP3 inflammasome activation mainly by triggering SIRT3-mediated mitophagy.

中文翻译：

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右美托咪定通过激活 SIRT3 介导的线粒体自噬和抑制幼鼠 NLRP3 炎性体的激活来改善由肝缺血/再灌注引起的海马损伤和认知功能障碍

肝缺血再灌注 (HIR) 已被证明会引发海马中的氧化应激和细胞焦亡。Sirtuin 3 (SIRT3) 是一种重要的线粒体蛋白脱乙酰酶，可调节氧化应激和线粒体自噬。右美托咪定 (Dex) 已被证明在不同的脑损伤模型中具有神经保护作用。然而，HIR 后 Dex 的保护作用是否是通过激活 SIRT3 介导的线粒体自噬和抑制 NOD 样受体蛋白 3 (NLRP3) 炎症小体激活来协调的仍然未知。在此，两周大的大鼠用 Dex 或选择性 SIRT3 抑制剂 (3-TYP)/自噬抑制剂 (3-MA) 治疗，然后进行 HIR。结果表明，Dex 治疗通过上调 SIRT3 的表达和活性有效地减轻了神经炎症和认知缺陷。此外，Dex 处理抑制了 NLRP3 炎性体的激活，而 3-TYP 和 3-MA 消除了 Dex 的保护作用，表明 SIRT3 介导的线粒体自噬发挥了 Dex 的保护作用。此外，3-TYP 处理下调 SIRT3 下游蛋白的表达水平：叉头盒蛋白 3α (FOXO3 α )、超氧化物歧化酶 2 (SOD2)、过氧化还原蛋白 3 (PRDX3) 和亲环蛋白 D (CYP-D)，它们几乎不受 3-MA 处理的影响。值得注意的是，3-TYP 和 3-MA 都能够抵消 Dex 的抗氧化和抗凋亡作用，表明 SIRT3 介导的线粒体自噬可能是执行 Dex 神经保护作用的最后一步和主要途径。总之，Dex 主要通过触发 SIRT3 介导的线粒体自噬来抑制 HIR 诱导的 NLRP3 炎性体激活。