Superoxide, no, peroxynitrite and PARP in circulatory shock and inflammation
Emanuela Esposito1,2, Salvatore Cuzzocrea2,3
1
Department of Experimental Pharmacology, University of Naples "Federico II", Via D. Montesano 49, Naples, Italy, 2IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy, 3Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. Background
- 4.Superoxide
- 4.1. Superoxide dismutase
- 4.2. Superoxide Dismutase Mimetics
- 4.2.1. Manganese (III) Metalloporphyrins
- 4.2.2. Manganeseiii (Salen) Complexes
- 4.2.3. Nitroxides
- 4.2.4. Manganese (II) (pentaazamacrocyclic ligand)-based complexes
- 4.3. Superoxide dismutase: preclinical and clinical experience
- 4.4. Superoxide dismutase mimetics and hydrogen peroxide-driven toxicity
- 5. Nitric oxide
- 5.1. NOS inhibitors
- 6. Peroxynitrite
- 6.1. Peroxynitrite decomposition catalyst
- 7. PARP37
- 7.1. PARP inhibitors
- 7.2. PARG inhibitor
- 8. Perspective
- 9. References
1. ABSTRACT
Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. 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 tissue injury associated with circulatory shock and inflammation. Reactive oxygen species (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 (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Moreover, Poly (ADP-ribosyl)ation is regulated by the synthesizing enzyme poly (ADP-ribose) polymerase-1 (PARP-1) and the degrading enzyme poly (ADP-ribose) glycohydrolase (PARG). Here we review the roles of ROS, PARP-1 and PARG in circulatory shock and inflammation as well as the beneficial effect of the in vivo treatment with novel pharmacological tools (e.g. peroxynitrite decomposition catalysts, selective superoxide dismutase mimetics (SODm), PARP-1 and PARG inhibitors.
