ROLE OF PEROXYNITRITE AND APOPTOSIS RELATED PROTEINS, p53 AND bcl-2, IN METHAMPHETAMINE-INDUCED NEUROTOXICITY

S. Z. Imam^a,*, Y. Itzhak^b, J. L Cadet^c, W. Slikker Jr.^a and S. F. Ali^a.

^aNeurochemistry  Laboratory, Division of Neurotoxicology, NCTR/FDA, Jefferson, AR 72079, ^bDepartment of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, FL 33101, ^cMolecular Neuropsychiatry Section, IRP/NIDA, Baltimore, MD 21224.

                 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 METH-induced peroxynitrite generation in the dopaminergic cell death pathway, we investigated the production of 3-nitrotyrosine (3-NT) in the mouse striatum. We also sought to determine if the production of 3-NT was related to the expression of the cell death related genes, p53 and bcl-2. 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 hr interval) as compared to 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. Moreover, METH treatment up-regulated the expression of p53 and down-regulated the expression of bcl-2 in the striatum of wild type mice. No significant alterations were observed in the expression of these proteins in the nNOS -/- and SOD-Tg mice. These data suggest that METH might cause its neurotoxic effects via the production of peroxynitrite and secondary perturbations in the expression of genes known to be involved in the cell death machinery. (Supported by US FDA/NCTR).

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