Dexmedetomidine Protects Rat Liver against Ischemia-Reperfusion Injury Partly by the α2A-Adrenoceptor Subtype and the Mechanism Is Associated with the TLR4/NF-κB Pathway

Abstract

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α2-adrenoceptor antagonists including atipamezole (a nonselective α2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway.

Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)

“…All three α2-subtypes adrenoceptors (ADRA2) including ADRA2A couple to inhibitory Gi proteins and modulate the downstream PI3K/Akt pathway to regulate multiple physiologic processes, such as neurotransmitter release, platelet aggregation, blood pressure, insulin secretion, and lipolysis [Ahles et al, 2014][Fagerholm et al, 2011]. ADRA2A also plays an important role in modulating the inflammatory process via TLR4/NF-κB pathways [Leong et al, 2010][Wang et al, 2016]. In our published work, we proved the roles of TLR/NF-κB-CXCR4/7 pathway and PI3K/Akt pathway in human ASH and NASH specimen with MDB formation.…”

Dexmedetomidine Postconditioning Alleviates Hypoxia/Reoxygenation Injury in Senescent Myocardial Cells by Regulating lncRNA H19 and m6A Modification

“…Perioperative trauma, stress, and anesthesia increase the risk for I/R injury, especially in elderly patients, whose systemic physiological function is decreased, tolerance to surgery and anesthesia are reduced, and cardiovascular adverse events are incremental [2]. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, protects organs from I/R injury by several mechanisms [3][4][5][6]. As such, it is widely used as anesthesia for cardiovascular surgery; indeed, perioperative Dex reportedly reduces the mortality rate at 1 year after surgery, as well as the incidence of postoperative complications and delirium following cardiac surgery [7].…”

Dexmedetomidine post‐treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF‐1α signalling

“…[11][12][13] In addition to its cardioprotective benefits, DEX has been found to attenuate I/R injury in other vital organs, including the brain, liver, kidney, lungs and spinal cord. [34][35][36][37][38] Few studies have investigated the effects of DEX post-treatment; however, administration at the onset of reperfusion is more applicable in clinical practice. A previous study failed to show the protective effect of DEX post-treatment against myocardial injury.…”