Isoglycyrrhizinate magnesium enhances hepatoprotective effect of FK506 on ischemia-reperfusion injury through HMGB1 inhibition in a rat model of liver transplantation.

Background: Ischemia-reperfusion injury (IRI) after liver transplantation impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after IRI in a rat model of liver transplantataion. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. Methods: Rats after liver transplantation were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. ALT, AST and albumin level were measured after 48h, 72h and 7days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. Results: Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506+Iso was better for maintenance of liver function than lower-dose FK506 alone at 48h, 72h and 7days after liver transplantation. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. But autophagy induced by FK506 also lead to high-mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. Conclusions: Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat liver transplantation. Combining Iso with FK506 would be promising for the patients after liver transplantation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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