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Methamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of
S Z Imam1, J P Crow, G D Newport
1Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Rd., Jefferson, AR 72079, USA.
Abstract:
Methamphetamine (METH)-induced dopaminergic neurotoxicity is believed to be produced by oxidative stress and free radical generation. The present study was undertaken to investigate if METH generates peroxynitrite and produces dopaminergic neurotoxicity. 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. Administration of METH resulted in the significant formation of 3-nitrotyrosine (3-NT), an in vivo marker of peroxynitrite generation, in the striatum and also caused a significant increase in the body temperature. METH injection also caused a significant decrease in the concentration of dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) by 76%, 53% and 40%, respectively, in the striatum compared with the control group. Treatment with FeTMPyP blocked the formation of 3-NT by 66% when compared with the METH group. FeTMPyP treatment also provided significant protection against the METH-induced hyperthermia and depletion of DA, DOPAC and HVA. Administration of FeTMPyP alone neither resulted in 3-NT formation nor had any significant effect on DA or its metabolite concentrations. These findings indicate that peroxynitrite plays a role in METH-induced dopaminergic neurotoxicity and also suggests that peroxynitrite decomposition catalysts may be beneficial for the management of psychostimulant abuse.
Insights
Methamphetamine (METH) generates peroxynitrite, causing neurotoxicity. A catalyst, FeTMPyP, blocked this, protecting dopamine levels and suggesting a treatment for stimulant abuse.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Methamphetamine (METH) neurotoxicity is linked to oxidative stress.
- The role of peroxynitrite in METH-induced dopaminergic neurotoxicity requires further investigation.
Purpose of the Study:
- To determine if METH generates peroxynitrite and causes dopaminergic neurotoxicity.
- To evaluate the neuroprotective potential of FeTMPyP, a peroxynitrite decomposition catalyst, against METH toxicity.
Main Methods:
- Administration of METH to induce neurotoxicity and measured 3-nitrotyrosine (3-NT) as a marker of peroxynitrite.
- Assessed changes in dopamine (DA) and its metabolites (DOPAC, HVA) in the striatum.
- Investigated the effect of FeTMPyP treatment on 3-NT formation, hyperthermia, and DA depletion.
Main Results:
- METH administration significantly increased 3-NT formation and body temperature.
- METH significantly depleted striatal DA, DOPAC, and HVA concentrations.
- FeTMPyP treatment blocked 3-NT formation by 66% and protected against METH-induced hyperthermia and neurochemical deficits.
Conclusions:
- Peroxynitrite plays a significant role in METH-induced dopaminergic neurotoxicity.
- Peroxynitrite decomposition catalysts, like FeTMPyP, show potential therapeutic benefits for managing psychostimulant abuse.