ELEVATED EXPRESSION OF GLUTATHIONE-PEROXIDASE IN PC12 CELLS RESULTS IN PROTECTION AGAINST METHAMPHETAMINE BUT NOT MPTP TOXICITY

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydrop yridine (MPTP) or methamphetamine (MA) produces damage to the dopamine rgic nervous system which may be due in part to the generation of reac tive oxygen species (ROS). The resistance of superoxide dismutase (SOD ) over-expressing transgenic mice to the effects of both MPTP and MA s uggests the involvement of superoxide in the resulting neurotoxicity o f both compounds. Superoxide can be converted by SOD to hydrogen perox ide, which itself can cause cellular degeneration by reacting with fre e iron to produce highly reactive hydroxyl radicals resulting in damag e to proteins, nucleic acids and membrane phospholipids. Hydrogen pero xide has also been reported to be produced via inhibition of NADH dehy drogenase by MPP + formed during oxidation of MPTP by MAO-B and by dop amine auto-oxidation following MA-induced dopamine release from synapt ic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotox ins, we created clonal PC12 lines expressing elevated levels of the hy drogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevat ion of GSHPx levels in PC12 was found to diminish the rise in ROS leve ls and lipid peroxidation resulting from MA but not MPTP treatment. El evated levels of GSHPx also appeared to prevent decreases in transport -mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide p roduction likely contributes to MA toxicity in dopaminergic neurons. ( C) 1997 Elsevier Science B.V. All rights reserved.