Research reportMethamphetamine generates peroxynitrite and produces dopaminergic neurotoxicity in mice: protective effects of peroxynitrite decomposition catalyst
Introduction
Methamphetamine (METH) is a drug that is significantly abused worldwide. It causes neurotoxicity in rodents and non-human primates by producing long-term depletion of dopamine (DA) and its metabolites 2, 16, 33, decreases number of DA transporter binding sites [18], and tyrosine hydroxylase (TH) activity [23] in the striatum. DA transporters are also reduced in the post-mortem striatum of chronic METH users [41]. There are two major findings suggesting the role of excitatory amino acid (EAA) transmission in METH-induced neurotoxicity. First, blockade of the N-methyl-d-aspartate (NMDA) type of glutamate receptors by dizocilpine (MK-801) attenuates METH-induced neurotoxicity 2, 36, 40. Second, repeated administration of METH causes an increase in glutamate release in the striatum [26]. The fact that EAA receptor antagonists modulate the development of amphetamine-induced behavioral sensitization further supports the role of glutamatergic neurotransmission in the effects of these psychostimulants [22]. Interaction of glutamate with the NMDA receptor complex opens channels that admit calcium into the cell; binding of calcium to calmodulin activates neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) [11]. Recently, we and others have reported that a selective nNOS inhibitor, 7-nitroindazole protects against the METH-induced dopaminergic neurotoxicity 10, 18 which implicates the role of NO radicals in METH neurotoxicity. To further investigate, we also demonstrated that nNOS knock-out mice are protected from METH-induced dopaminergic neurotoxicity [20] and antioxidants like selenium [16] and melatonin [19] can attenuate METH-induced dopaminergic neurotoxicity. There are several reports in the literature which discuss the involvement of superoxide (O2·−) radicals in METH-induced neurotoxicity [6]. It has been reported that METH-induced DA depletion is attenuated in copper–zinc superoxide dismutase over expressed transgenic mice 7, 8. Therefore, the possibility of the interaction between O2·− and NO may not be ruled out in case of METH-induced neurotoxicity.
Peroxynitrite (OONO−), the reaction product of O2·− and NO, is a potent oxidant [29]. A compelling body of evidence has begun to emerge that suggests that OONO− forms in significant concentrations in vivo. In addition, it has now been demonstrated clearly that OONO− is capable of oxidizing lipid membranes 29, 30 and sulfhydryl moities [28], as well as hydroxylating and nitrating aromatics 38, 39. Because of its high reactivity under physiological conditions, direct measurement of OONO− in vivo is not achieved easily. However, the nitration of tyrosyl residues has been shown to be a stable biochemical marker of OONO− production both in vitro and in vivo 4, 17. Stern et al. [37] discovered that various iron porphyrins catalyze the efficient decomposition of OONO− to nitrate under physiological conditions [15]. These iron porphyrins have profound activity in biological models of OONO− related disease states and have been investigated as therapeutic agents for diseases in which OONO− has been implicated 31, 37. One of these iron porphyrins is 5, 10,15,20-tetrakis(N-methyl-4′-pyridyl)porphyrinato iron III (FeTMPyP). The present study was designed to investigate whether METH-induced neurotoxicity is mediated by OONO− by measuring 3-nitrotyrosine (3-NT) and its correlation with METH-induced dopaminergic changes and whether the use of peroxynitrite decomposition catalyst FeTMPyP can protect against the METH-induced dopaminergic neurotoxicity.
Section snippets
Drugs and chemicals
METH HCl, DA, DOPAC, HVA and FeTMPyP were purchased from Sigma (St. Louis, MO, USA). Tyrosine (TYR), 3-NT were purchased from Calbiochem (La Jolla, CA, USA). METH HCl and FeTMPyP solution were prepared in deionized water.
Animals and schedule of drug administration
Adult male C57BL/J6N mice (30–32 g; NCTR Breeding Colony) were maintained on a 12-h light–dark lighting schedule, at a room temperature of 21°C±1°C and housed in groups of four with free access to food and water. Animals were divided into four groups (n=8/group). Group 1
Results
The effects of FeTMPyP treatment on the levels of 3-NT in the striatum of METH-treated animals has been summarized in Fig. 1. 3-NT values represent the number of TYR analogues being nitrated by the peroxynitrite per 100 TYRs. Almost no formation of 3-NT was observed in control group. Administration of METH (4×10 mg/kg, i.p.) resulted in the marked significant formation of 3-NT in the striatum as compared to control group. FeTMPyP treatment significantly protected against the METH-induced
Discussion
The present study reports that the administration of METH caused the generation of peroxynitrite which resulted in the significant formation of 3-NT in the striatal tissue and this increase of 3-NT can be protected by treatment of FeTMPyP. Furthermore, treatment with FeTMPyP also protected against METH-induced increase in body temperature and METH-induced depletion of striatal DA and its metabolites DOPAC and HVA.
The role of O2·− and NO has been well documented in case of METH-induced
Acknowledgements
This research was supported in part by an appointment (S.Z.I) to the Research Participation Program at the National Center for Toxicological Research administered by the Oak Ridge Institute of Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.
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