Intravenous Administration of Geranylgeranylacetone Effectively Prevents Ischemia-Reperfusion Injury of Rat Livers
Abstracts
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BACKGROUND/AIMS: In the last meeting, we showed that a single oral administration of 100 mg/kg geranylgeranylacetone (GGA) significantly improved survival of rats received 95% hepatectomy. Using warm ischemia model of rat livers, we tested whether GGA could suppress ischemia-reperfusion injury of rats. Furthermore, we examined the most effective method for the treatment with this non-toxic heat shock protein 70 (HSP70) inducer. METHODS: Male Wistar rats (220 to 250 g) were subjected to 30-min warm ischemia by the maneuver of Pringle. Two to eight hours before the ischemia, various doses of GGA (50 to 400 mg/kg) were intragastrically administrated. A single intravenous administration of GGA (0.1 to 2 mg/kg) was done via caudal vein 2 to 8 hours before the maneuver of Pringle. Before and 2, 4, 6, 8, 12, or 24 hours after reperfusion, HSP70 levels in the left hepatic lobe were measured by Western blotting and immunohistochemistry with an anti-HSP70 antibody. The activities of serum transaminases (AST and ALT) were measured using an autoanalyzer, and the levels of TNF-alpha, IL-1-beta, and IL-6 were assayed by the ELISA methods. RESULTS: As judged by the magnitude of transaminase releases, the optimal dose and best timing of oral administration of GGA were determined to be 100 mg/kg and 4 hours prior to the ischemia, respectively. Similarly, with regard to intravenous treatment, the most effective protection was achieved by the treatment with 1 mg/kg GGA 4 hours before starting the ischemia. The intravenous treatment more effectively suppressed the ischemia-reperfusion injury than oral administration, which was assessed by the extent of HSP70 induction, transaminase releases, and productions of the inflammatory cytokines. CONCLUSION: Our results suggest that GGA also prevents acute hepatic injury after ischemia-reperfusion by specifically inducing HSP70 and by suppressing the production of inflammatory cytokines. The optimal dose of GGA could be reduced to clinically practical one by intravenous administration. Furthermore, intravenous administration (1 mg/kg) exerted cytoprotective action of GGA more effectively than oral administration. |
