Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury

Background and aim: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappa B)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a pminflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75 mu g/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-kappa B dependent manner. Methods: Rats were randomized into sham, HIR, OCT (50, 75, and 100 mu g/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. Results: OCT pretreatment at doses (50 or 75 mu g/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented antioxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-I kappa B alpha (532), p-NF-kappa Bp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. Conclusion: OCT at doses (50 or 75 mu g/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-kappa B/NLRP3 inflammasome pathway.

Automated summary

This study demonstrated that pretreatment with octreotide (OCT) at different doses or OCT at 75 μg/kg combined with melatonin (MLT) can alleviate hepatic ischemia/reperfusion injury by targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-kappa B dependent manner. OCT at doses (50 or 75 μg/kg) showed a hepatoprotective effect against HIR injury through inhibiting TLR4-NLRP3-mediated pyroptosis in rats, with OCT75 being more effective than OCT50 or MLT alone.