Methamphetamine‐Induced Dopaminergic Neurotoxicity: Role of Peroxynitrite and Neuroprotective Role of Antioxidants and Peroxynitrite Decomposition Catalysts

Abstract

Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half‐lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3‐nitrotyrosine (3‐NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent‐driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3‐NT in the striatum. This formation of 3‐NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3‐NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3‐NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20‐tetrakis(N‐methyl‐4′‐pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20‐tetrakis (2,4,6‐trimethyl‐3,5‐sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH‐induced 3‐NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7‐nitroindazole (7‐NI), significantly protect against the formation of 3‐NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)‐overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH‐induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH‐induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…Like other amphetamines, methamphetamine increases extracellular levels of monoamines by disrupting vesicular storage and reversing the plasma membrane transporter [262][263][264]. While methamphetamine's effects upon the monoaminergic systems have received considerable experimental attention [for reviews, [264][265][266][267][268][269][270], less is known regarding the regulation of corticoaccumbens glutamate and glutamate receptor expression by amphetamine and methylated analogs. Acute administration of amphetamines is reported to produce either no change or a delayed rise in extracellular glutamate levels within striatal regions [59][60][61][62]271,272], while an acute injection of methamphetamine, but not amphetamine, elevates PFC glutamate levels [271].…”

Oxidative Stress and Neurotoxicity

“…There is evidence that oxidative stress arises from peroxidative generation of dopamine quinone from dopamine released by METH into the cytoplasm from synaptic vesicles via reverse transport through the dopamine transporter (257,258). RNS (peroxynitrite) also appear to play a major role in METH-induced dopaminergic neurotoxicity (259).…”

Dynamic Changes in Vesicular Glutamate Transporter 1 Function and Expression Related to Methamphetamine-Induced Glutamate Release

“…METH-induced increases in extracellular concentrations of striatal DA and GLU (O'Dell et al, 1991;Stephans and Yamamoto, 1994) are known to contribute to the observed nerve terminal damage (Sonsalla et al, 1989;Nash and Yamamoto, 1992;Imam et al, 2001). Unlike METH-induced striatal DA release, which occurs directly via reverse transport, METH-induced striatal GLU release is indirect and initiated by the activation of the D 1 -associated striatonigral GABAergic pathway (Mark et al, 2004).…”