Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: Implications for the prevention of methamphetamine-induced neurotoxic damage

Syed Z. Imam, Fakhrul Islam, Yossef Itzhak, William Slikker, Syed F. Ali

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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(2,4,6trimethyl-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.

Original languageEnglish
Pages (from-to)157-171
Number of pages15
JournalAnnals of the New York Academy of Sciences
Volume914
StatePublished - Dec 4 2000

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Peroxynitrous Acid
Methamphetamine
Nitric Oxide
Nitric Oxide Synthase Type I
Induced Hyperthermia
Decomposition
Catalysts
Reactive Oxygen Species
Nitrogen
Oxygen
Oxidative stress
Damage
Free Radicals
Brain
Oxidative Stress
Iron

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite : Implications for the prevention of methamphetamine-induced neurotoxic damage. / Imam, Syed Z.; Islam, Fakhrul; Itzhak, Yossef; Slikker, William; Ali, Syed F.

In: Annals of the New York Academy of Sciences, Vol. 914, 04.12.2000, p. 157-171.

Research output: Contribution to journalArticle

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