α-Lipoic Acid Attenuates Ischemia Reperfusion Injury of the Rat Liver

107 Ischemia reperfusion injury (IRI) represents a major clinical
problem in liver transplantation and resection. Main
pathophysiological events during this injury comprise depletion of
ATP, Kupffer cell activation with subsequent formation of reactive
oxygen species and inflammatory response. Depending on the severity
of IRI, cell damage leads to necrotic or apoptotic liver cell
death, resulting in organ dys- or even nonfunction. The present
work investigated the potential of α-lipoic acid (LA), a well
established agent in the therapy of diabetic polyneuropathy, to
reduce IRI of the rat liver. In the system of the isolated perfused
rat liver, an experimental model of hepatic IRI, LA was utilized in
different treatment protocols and concentrations. As a key result
of this study, pre- as well as postischemic treatment with LA was
shown for the first time to markedly reduce hepatic IRI. Further
investigations characterized the underlying mechanisms of LA
action, focussing on the preconditioning protocol. Thereby, LA was
shown to increase hepatic ATP content during ischemia and
reperfusion, suggesting a better energy availability in these
organs. Activation of the redox-sensitive transcription factors
NF-κB and AP-1 was reduced by LA, suggesting a decreased
inflammatory response of the liver. Most importantly, this work
describes for the first time that the protein kinase Akt plays a
crucial role in IRI. The cytoprotective kinase was activated by LA
preconditioning during ischemia and reperfusion. Blocking Akt
activation by simultaneous application of wortmannin, a selective
PI-3 kinase inhibitor, abrogated the LA preconditioning effect,
showing a causal involvement of Akt in LA-mediated protection from
IRI. Therefore, Akt activation can be regarded as a new protective
mechanism in hepatic IRI. To conclude, LA treatment might represent
a new pharmacological approach in attenuating IRI of the liver.