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Increased expression of monoamine oxidase-B results in enhanced neurite degeneration in methamphetamine-treated PC12
Q Wei1, O P Jurma, J K Andersen
1Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles, USA.
Abstract:
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.
Insights
Methamphetamine (MA) damages dopamine neurons by releasing dopamine, which generates damaging reactive oxygen species (ROS). Inhibiting monoamine oxidase (MAO) with deprenyl reversed MA-induced neurite degeneration.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Methamphetamine (MA) causes selective damage to dopaminergic nerve terminals.
- This damage is hypothesized to involve dopamine release and subsequent reactive oxygen species (ROS) generation.
- ROS, such as hydroxyl radicals formed from hydrogen peroxide and iron, can oxidize cellular components, leading to neurodegeneration.
Purpose of the Study:
- To investigate the role of dopamine metabolism and ROS production in MA-induced neurotoxicity.
- To examine the effects of elevated monoamine oxidase (MAO) activity on MA-induced cellular damage in dopaminergic neurons.
Main Methods:
- Utilized nerve growth factor-treated PC12 cells to model dopaminergic neurons.
- Manipulated monoamine oxidase (MAO) activity and treated cells with methamphetamine (MA).
- Assessed dopamine metabolism products, lipid peroxidation, and neurite morphology.
- Investigated the effects of the MAO-B inhibitor, deprenyl.
Main Results:
- Elevated MAO activity increased dopamine metabolism products (e.g., 3,4-dihydroxyphenylacetic acid, hydroperoxides) and lipid peroxidation after MA treatment.
- MA treatment led to decreased neurite number and length in PC12 cells.
- Deprenyl treatment reversed the MA-induced decrease in neurite integrity.
Conclusions:
- Dopamine metabolism and subsequent ROS production are critical mechanisms in MA-induced neurite degeneration.
- MAO activity plays a significant role in mediating MA neurotoxicity.
- MAO-B inhibition may offer a protective strategy against methamphetamine-induced dopaminergic neurotoxicity.