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Role of Poly(ADP-Ribose) Polymerase Activation in the Pathogenesis of Inflammation and Circulatory Shock

  • Csaba Szabó
Part of the Molecular Biology Intelligence Unit book series (MBIU)

Abstract

Oxidative and nitrosative stress triggers DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Activation of PARP may dramatically lower the intracellular concentration of its substrate, nicotinamide adenine dinucleotide, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. Here I review the impact of pharmacological inhibition or genetic inactivation of PARP on the course of various forms of shock and inflammation in vivo. A major trigger for DNA damage in pathophysiological conditions is peroxynitrite, a cytotoxic oxidant formed by the reaction between the free radicals nitric oxide and superoxide. Here I review (a) some of the evidence supporting the production of DNA-damaging oxygen- and nitrogen-derived oxidants and free radicals and oxidants in various forms of shock and inflammation, (b) the evidence demonstrating PARP activation in these conditions and (c) the effects of pharmacological inhibition or PARP or genetic deficiency of PARP-1. Pharmacological inhibition of PARP emerges as a novel approach for the experimental therapy of various forms of inflammation and shock.

Keywords

Nitric Oxide Hemorrhagic Shock Experimental Allergic Encephalomyelitis PARP Inhibitor Endotoxic Shock 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Csaba Szabó
    • 1
  1. 1.Inotek Pharmaceuticals CorporationBeverlyUSA

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