Increased expression of monoamine oxidase-B results in enhanced neurite degeneration in methamphetamine-treated PC12 cells.
In vivo administration of methamphetamine (MA) produces selective damage to dopaminergic nerve terminals, which is hypothesized to be due to release of dopamine from synaptic vesicles within the terminals, allowing the generation of reactive oxygen species (ROS) via dopamine metabolism. Hydrogen peroxide formed during this reaction can interact with free iron to form hydroxyl radicals, which can oxidize proteins, nucleic acids, and membrane lipids, leading to terminal degeneration. Elevation of activity of the dopamine-metabolizing enzyme monoamine oxidase (MAO) in nerve growth factor-treated PC12 cells resulted in a substantial rise in products of dopamine metabolism following MA treatment, including 3,4-dihydroxyphenylacetic acid and hydroperoxides, as well as an increase in lipid peroxidation and a decrease in neurite number and length compared with control cells. These latter effects could be reversed by treatment with the MAO-B specific inhibitor, deprenyl. These data suggest that dopamine metabolism and subsequent ROS production may be key elements in MA-induced neurite degeneration in dopaminergic neurons.
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Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles, USA.
Jurma
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Andersen
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology*; D008995:Monoamine Oxidase / Q000096:biosynthesis*; D009410:Nerve Degeneration / Q000503:physiopathology*; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats
D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D004298:Dopamine