Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats

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.

The Protective Effect of Dexmedetomidine Against Ischemia-Reperfusion Injury after Hepatectomy: A Meta-Analysis of Randomized Controlled Trials

“…Thus, additional researches involving renal function as an outcome are needed to further evaluate the protective effect of dexmedetomidine in renal injury induced by hepatic IR. In preclinical studies, the protective effect of dexmedetomidine was also observed in the lungs, kidneys and brain (Tüfek et al, 2013;Yu et al, 2020). Thus, further clinical trials may involve the evaluation of dexmedetomidine effect on more remote organs.…”

Protective effects of dexmedetomidine in vital organ injury: crucial roles of autophagy

“…A growing body of research has revealed that autophagy might be involved in the organ-protective actions of DEX [ 20 , 21 ]. Autophagy, an adaptive catabolic process, functions to maintain cellular homeostasis by engulfing cellular targets, including damaged organelles, unfolded proteins, and pathogens [ 22 – 24 ].…”

“…A data collection table was applied to extract the key data from the relevant studies, including the first author’s name, publication year, geographical distribution, cell/animal model, types of organ injury, DEX administration, autophagy status, associated genes or pathways, and the main findings of the included studies. Finally, 24 studies [ 21 , 27 – 30 , 41 – 59 ] were included. Among these, 14, 4, 3, and 3 eligible studies reported cerebral injury, myocardial injury, kidney injury, and lung injury, respectively.…”

Corrigendum to “Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats”

“…In the article titled “Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats” [ 1 ], a number of errors have been identified, which should be corrected as follows: In Section 2.2, paragraph 7, “(4) 3-TYP group where they were pretreated with 3-TYP then treated with 20 μ g/kg Dex before hepatic ischemia” should be corrected to, “(4) 3-TYP group where they were pretreated with 3-TYP then treated with 25 μ g/kg Dex before hepatic ischemia”. The third limitation in paragraph 47 of the Discussion should not have appeared in the published article, “the study only focused on SIRT3 expression without considering other SIRT families.…”

“…In the article titled "Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats" [1], a number of errors have been identified, which should be corrected as follows:…”