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Vol. 53, Issue 1, 135-159, March 2001

Antioxidant Therapy: A New Pharmacological Approach in Shock, Inflammation, and Ischemia/Reperfusion Injury

Salvatore Cuzzocrea1, Dennis P. Riley, Achille P. Caputi and Daniela Salvemini

Institute of Pharmacology, University of Messina, Messina, Italy (S.C., A.P.C.); and Metaphore Pharmaceuticals, St. Louis, Missouri (D.P.R., D.S.)

I. Introduction
    A. Oxygen Radical
    B. Nitrogen Species
II. DNA Damage
III. Poly(ADP-Ribose) Synthetase
IV. Relative Importance of Reactions of Glutathione with Nitric Oxide, Oxyradicals, and Peroxynitrite in Endotoxic Shock and Inflammation
V. Superoxide Dismutase
VI. Radical Generation
    A. In Ischemia/Reperfusion
    B. In Shock and Inflammation
VII. Pharmacological Intervention to Reduce Reactive Oxygen Species Generation in Shock, Inflammation, and Ischemia/Reperfusion
    A. Peroxynitrite Decomposition Catalysts as Anti-inflammatory Agents
    B. Catalytic Antioxidants
    C. Metalloporphyrins
        1. Effects of Metalloporphyrins in Inflammation.
        2. Effect of Metalloporphyrins in Endotoxic and Hemorrhagic Shock.
        3. Limitations of Metalloporphyrins.
    D. New Rational Synthetic Enzymes: Manganese(II)-Based Superoxide Dismutase Mimics
        1. Characterization of Superoxide Dismutase Activity.
        2. Catalyst/Drug Design.
        3. Anti-Inflammatory Activity of Superoxide Dismutase Mimics.
        4. Attenuation of Myocardial Ischemia/Reperfusion Injury by Superoxide Dismutase Mimics.
VIII. Conclusions and Future Directions
References

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock, and ischemia/reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species (ROS) in shock, inflammation, and ischemia/reperfusion injury. The second part of the review deals with the novel findings using recently identified pharmacological tools (e.g., peroxynitrite decomposition catalysts and selective superoxide dismutase mimetics (SODm) in shock, ischemia/reperfusion, and inflammation. 1) The role of ROS consists of immunohistochemical and biochemical evidence that demonstrates the production of ROS in shock, inflammation, and ischemia/reperfusion injury. ROS can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation, and ischemia/reperfusion. 2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm, which selectively mimic the catalytic activity of the human superoxide dismutase enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock, inflammation, and ischemia/reperfusion injury. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase, leading to eventual severe energy depletion of the cells and necrotic-type cell death. Antioxidant treatment inhibits the activation of poly(ADP-ribose) synthetase and prevents the organ injury associated with shock, inflammation, and ischemia/reperfusion.

1 Address for correspondence: Salvatore Cuzzocrea, Ph.D., Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C. Valeria-Gazzi, 98100 Messina, Italy. E-mail: salvator{at}www.unime.it

0031-6997/01/5301-0135$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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