Abstract
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.
Highlights
Liver transplantation is the standard treatment for children with advanced liver disease
The rats were further randomly divided into the following groups (n = 50): (1) sham operation group (S group), (2) IR group, (3) DEX group where they were treated with 25 μg/kg Dex before hepatic ischemia, (4) 3-TYP group where they were pretreated with 3-TYP treated with 20 μg/kg Dex before hepatic ischemia, and (5) 3-MA group where rats were pretreated with 3-MA treated with 25 μg/kg Dex before hepatic ischemia
To determine whether sirtuins play a role in the hippocampus injury induced by Hepatic ischemia-reperfusion (HIR), we first determined the protein levels of sirtuin 1 (SIRT1), sirtuin 2 (SIRT2), Sirtuin 3 (SIRT3), SIRT6, and SIRT7 in the hippocampus after 60 minutes of ischemia with various lengths of reperfusion
Summary
Liver transplantation is the standard treatment for children with advanced liver disease. The 1- and 5-year survival rates after liver transplantation are currently at about 95% and 85%, respectively [1], neurological complications are still prevalent after surgery and affect 15%-30% of liver transplant recipients [2]. Neurological injuries in early life translate to long-lasting developmental consequences [5]. Hepatic ischemia-reperfusion (HIR) is an essential step in liver transplantation and has an important effect on early liver allograft dysfunction and long-term graft survival. This mediates liver and remote organ injury [6, 7]. The mechanisms involved in hippocampus injury induced by HIR remain unclear
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