Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase.
The use of methamphetamine (METH) leads to neurotoxic effects in mammals. These neurotoxic effects appear to be related to the production of free radicals. To assess the role of peroxynitrite in METH-induced dopaminergic, we investigated the production of 3-nitrotyrosine (3-NT) in the mouse striatum. The levels of 3-NT increased in the striatum of wild-type mice treated with multiple doses of METH (4 x 10 mg/kg, 2 h interval) as compared with the controls. However, no significant production of 3-NT was observed either in the striata of neuronal nitric oxide synthase knockout mice (nNOS -/-) or copper-zinc superoxide dismutase overexpressed transgenic mice (SOD-Tg) treated with similar doses of METH. The dopaminergic damage induced by METH treatment was also attenuated in nNOS-/- or SOD-Tg mice. These data further confirm that METH causes its neurotoxic effects via the production of peroxynitrite.
Imam
S Z
SZ
Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, Arkansas, USA.
Newport
G D
GD
Itzhak
Y
Y
Cadet
J L
JL
Islam
F
F
Slikker
W
W
Ali
S F
SF
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009498:Neurotoxins / Q000494:pharmacology*; D009566:Nitrates / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D012016:Reference Values; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D009566:Nitrates; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008694:Methamphetamine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D013482:Superoxide Dismutase; D004298:Dopamine