Role of free radicals and poly(ADP-ribose)polymerase-1 in the development of spinal cord injury: new potential therapeutic targets.
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 secondary damage associated with spinal cord injury. 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 spinal cord injury 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.
Genovese
T
T
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Cuzzocrea
S
S
D000818:Animals; D005609:Free Radicals / Q000009:adverse effects*; D005978:Glutathione / Q000502:physiology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008665:Metalloporphyrins / Q000627:therapeutic use; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D013119:Spinal Cord Injuries / Q000139:chemically induced* / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000502:physiology
D005609:Free Radicals; D008665:Metalloporphyrins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; D013482:Superoxide Dismutase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; D005978:Glutathione