title: Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage.
abstract: Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. 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. 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. 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). 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. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. 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.
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, USA.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Imam
authors.forename: F
authors.initials: F
authors.lastname: Islam
authors.forename: Y
authors.initials: Y
authors.lastname: Itzhak
authors.forename: W
authors.initials: W
authors.lastname: Slikker
authors.forename: S F
authors.initials: SF
authors.lastname: Ali
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D016166:Free Radical Scavengers / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000627:therapeutic use; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D018765:Dopamine Uptake Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D007191:Indazoles; D018696:Neuroprotective Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D030421:Peroxynitrous Acid; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D014443:Tyrosine; D008694:Methamphetamine; C080122:7-nitroindazole; D004298:Dopamine; D006719:Homovanillic Acid