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02 May 2003

PARP-inhibitors for ischemia-reperfusion injury of the liver

H. Mota-Filipe

Med Sci Monit 2003; 9(1): 46- :: ID: 15109


Ischemia-reperfusion (I/R) is responsible for the development of liver dysfunction and failure in several clinical conditions including liver transplantation and hemorrhagic shock. At the present, there is no pharmacological intervention proven to either attenuate liver cell injury or to augment tissue regeneration of the liver after acute or chronic injury of this organ. The occurrence of oxidant-mediated damage resulting from I/R has been demonstrated in several different animal models [1,2], where the generation of reactive oxygen species contributes to DNA damage [3]. One possible way of oxidant-induced injury involves the excessive activation of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP).Using a rat model of liver I/R, we have the effects of the water-soluble PARP-inhibitor 5-aminoisoquinoline (5-AIQ) on liver injury (transaminases, histopathology), the upregulation of the adhesion molecule intracellular adhesion molecule 1 (ICAM-1) and the increase in PARP activity (measured as immunoreactivity of PAR), and the degree of lipid peroxidation caused by ischaemia and reperfusion (I/R) of the liver. When compared to control, 5-AIQ reduced the I/R-induced rise in the serum levels of transaminases, lactate dehydrogenase, and g-glutamyl transferase as well as the degree of lipid peroxidation. Liver sections obtained from 5-AIQ treated rats showed reduced PARP activation and less staining for ICAM-1. The role that PARP plays in the process of recovery that follows I/R injury to the liver will be discussed. References: 1.Caldwell-Kendel JC, Currin RT, Tanaka Y et al: Reperfusion injury to endothelial cells following cold ischemic storage of rat livers. Hepatology, 1989; 10: 92-9 2.Schoenberg MH, Muhl E, Sellin D et al: Posthypotensive generation of superoxide free-radicals – possible role in the pathogenesis of the intestinal mucosal damage. Acta Chir Scand, 1984; 150: 301-9 3.Martin D, Lewington A, Hammerman M, Padanilam B: Inhibition of poly (ADP-ribose) polymerase attenuates ischemic renal injury in rats. Am J Physiol Regulatiry Integrative Comp Physiol, 2000; 279: 1834-40

Keywords: Liver, ischemia-reperfusion, PARP, 5-aminoisoquinoline

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750