In liver resection and
transplantation ischemia-reperfusion injury (IRI) is one of the main causes of organ dys- or nonfunction. The aim of the present study was to determine whether
alpha-lipoic acid (LA) is able to attenuate IRI. Rat livers were perfused with
Krebs-Henseleit buffer with or without LA (+/-
wortmannin), followed by
ischemia (1 h, 37 degrees C) and reperfusion (90 min). Efflux of
lactate dehydrogenase (LDH) and
purine nucleoside phosphorylase (PNP) and hepatic
ATP content were determined enzymatically. Activation of
NF-kappaB and activating
protein 1 (AP-1) was examined by EMSA, and
protein phosphorylation was examined by Western blot. Caspase-3-like activity served as an
indicator for apoptotic processes. Animals treated intravenously with 500 micromol LA were subjected to 90 min of partial no-flow
ischemia followed by reperfusion for up to 7 days. Preconditioning with LA significantly reduced LDH and PNP efflux during reperfusion in isolated perfused rat livers.
ATP content was significantly increased in LA-treated livers. Postischemic activation of
NF-kappaB and
AP-1 was significantly reduced in LA-pretreated organs. Preconditioning with LA significantly enhanced Akt phosphorylation. It showed neither effect on
endothelial nitric oxide synthase nor on Bad phosphorylation. Importantly, simultaneous administration of
wortmannin, an inhibitor of the
phosphatidylinositol (
PI)3-kinase/Akt pathway, blocked the protective effect of LA on IRI, demonstrating a causal relationship between Akt activation and hepatoprotection by LA. Interestingly, despite activation of Akt, LA did not reduce postischemic apoptotic cell death. The efficacy of LA treatment in vivo was shown by reduced GST plasma levels and improved liver histology of animals pretreated with LA. This study shows for the first time that the
PI3-kinase/Akt pathway plays a central protective role in IRI of the rat liver and that LA administration attenuates IRI via this pathway.