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

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet. 1. Overview and aim of this study Ischemia reperfusion injury (IRI) is a serious clinical problem during liver resections, liver transplantation, and haemorrhagic shock. The pathomechanisms of this injury can be divided into incidents during ischemia and events occuring during reperfusion. Some main pathophysiologic features of ischemic liver cell injury comprise depletion of ATP, disturbance of natrium-calcium homeostasis, and activation of phospholipase A 2 (Bilzer and Gerbes, 2000;Bilzer et al., 1994;Jaeschke et al., 1988). Reperfusion of livers leads to an aggravation of ischemic liver cell damage: reactive oxygen species (ROS) derived from activated Kupffer cells as well as the activation of proinflammatory, redox-sensitive transcription factors, such as NF-κB and AP-1, are discussed to contribute to hepatic reperfusion injury (Banafsche et al. Among substances with known antioxidative properties, α-lipoic acid (LA), a compound established in the therapy of diabetic polyneuropathy (Coleman Michael D., 2001), is especially interesting: LA exhibits distinct regulatory action on signal transduction processes playing a central role in tissue damage and protection. In this context the potential of LA to regulate stress-related signalling pathways, such as NF-κB and AP-1 on the one hand (Saliou et al., 1999), and to activate cytoprotective protein kinases on the other hand, has recently been reported (Yaworsky et al., 2000;Maddux et al., 2001). α-lipoic acid is found naturally occuring as a prosthetic group in α-keto acid dehydrogenase complexes of mitochondria, and therefore plays a fundamental role in metabolism. Administration of LA to cells leads to a rapid uptake and reduction to dihydrolipoic acid (DHLA) (Han et al., 1997). LA and DHLA are both potent scavengers of ROS, such as hydroxyl radical, hypochlorous acid or singlet oxygen, as well as effective metal chelators forming complexes with e.g.