![]() We also investigated if this generation of peroxynitrite can be blocked by a selective peroxynitrite decomposition catalyst, 5, 10,15, 20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and protect against METH-induced dopaminergic neurotoxicity. The present study was undertaken to investigate if METH generates peroxynitrite and produces dopaminergic neurotoxicity. Methamphetamine (METH)-induced dopaminergic neurotoxicity is believed to be produced by oxidative stress and free radical generation. Imam, S Z Crow, J P Newport, G D Islam, F Slikker, W Ali, S F Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of peroxynitrite decomposition catalyst. Together, these data demonstrate that METH-induced dopaminergic neurotoxicity is mediated by the generation of peroxynitrite, which can be selectively protected by nNOS inhibitors or peroxynitrite scavenger or decomposition catalysts. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. However, the use of a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), did not provide any significant protection against METH-induced hyperthermia or peroxynitrite generation and the resulting dopaminergic neurotoxicity. Significant protective effects were observed with the inhibitor of nNOS, 7-nitroindazole (7-NI), as well as by the selective peroxynitrite scavenger or decomposition catalyst, 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-sulfonatophenyl)porphyrinato iron III (FeTPPS). We have also assessed the effects of inhibitors of neuronal nitric oxide synthase (nNOS) as well as scavenger of nitric oxide and a peroxynitrite decomposition catalyst. In this study, we have obtained evidence that METH-induced neurotoxicity is the resultant of interaction between oxygen and nitrogen radicals, and it is mediated by the production of peroxynitrite. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. Imam, S Z Islam, F Itzhak, Y Slikker, W Ali, S F ![]() Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage. Neutralization of peroxynitrite with potent peroxynitrite decomposition catalysts provides cytoprotective and beneficial effects in rodent and large animal models of circulatory shock. Additional actions of peroxynitrite that contribute to the pathogenesis of shock include inactivation of catecholamines and catecholamine receptors (leading to vascular failure), endothelial and epithelial injury (leading to endothelial and epithelial hyper-permeability and barrier dysfunction) as well as myocyte injury (contributing to loss of cardiac contractile function). In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), which promotes cellular energetic collapse and cellular necrosis. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. In addition, biological markers of peroxynitrite have been identified in human tissues after circulatory shock. Immunohistochemical and biochemical evidence demonstrate the production of peroxynitrite in various experimental models of endotoxic and hemorrhagic shock, both in rodents and in large animals. Here we overview the role of peroxynitrite in various forms of circulatory shock. ![]() Summary Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with proteins, lipids and DNA and promotes cytotoxic and pro-inflammatory responses. Pathophysiological roles of peroxynitrite in circulatory shock ![]()
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