Geranylgeranylacetone, a heat shock protein inducer, prevents primary graft nonfunction in rat liver transplantation

Background. Heat shock proteins (HSPs) are well known as cytoprotective pro teins. Geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug, was recentl y shown to have HSP-inducing capacity. In the present study, the activity o f GGA was tested in a rat orthotopic liver transplantation (OLT) model to d etermine whether the compound has beneficial effects in warm ischemia-reper fusion injury. Methods. Either GGA or a control vehicle was orally administered to donor r ats before graft harvest. Harvested livers were subjected to 45-min warm is chemia (37 degreesC) followed by OLT. HSP mRNA expressions and HSP synthese s in the graft livers were evaluated by reverse transcriptase polymerase ch ain reaction and Western blot analysis, respectively. Results. When the donors were treated with a vehicle, all recipients died o f primary nonfunction within 2 days after OLT. In contrast, when the donors were treated with GGA (200 mg/kg per day) for 4 weeks, the 7-day survival rate of recipients was dramatically improved (90%). By giving a high dose o f GGA (600 mg/kg per day) for I week, a similar improvement in recipient su rvival was seen (83.3%). GGA administration accumulated mRNA for both HSP72 and HSP90 in the livers even before warm ischemia and facilitated the synt heses of HSP72 and HSP90 after warm ischemia. In addition, GGA pretreatment also significantly reduced the serum levels of tumor necrosis factor-alpha (TNF-alpha) after reperfusion. Conclusions. These findings indicate that both the enhanced induction of HS Ps and the suppression of a cytotoxic mediator (TNF-alpha) might be involve d in the beneficial effects of GGA on ischemia-reperfusion injury. Thus, or al administration of GGA would be a useful tool for preventing primary nonf unction in liver transplantation.