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Müller, Christian (2002): α-Lipoic Acid Attenuates Ischemia Reperfusion Injury of the Rat Liver: Mechanisms of Protection. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



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.