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Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: Mechanistic study

Ayadi, AE and Zigmond, MJ (2011) Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: Mechanistic study. PLoS ONE, 6 (10).

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Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [ 3H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD. © 2011 El Ayadi, Zigmond.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ayadi, AE
Zigmond, MJsurvival@pitt.eduSURVIVAL
ContributionContributors NameEmailPitt UsernameORCID
Date: 12 October 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0024722
Refereed: Yes
MeSH Headings: Animals; Cell Death--drug effects; Cell Line; Cytoprotection--drug effects; Dopamine--metabolism; Dopamine Plasma Membrane Transport Proteins--metabolism; Dopaminergic Neurons--drug effects; Dopaminergic Neurons--enzymology; Dopaminergic Neurons--pathology; Dose-Response Relationship, Drug; Enzyme Activation--drug effects; Extracellular Signal-Regulated MAP Kinases--antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases--metabolism; JNK Mitogen-Activated Protein Kinases--metabolism; Methamphetamine--pharmacology; Methamphetamine--toxicity; Mice; Mice, Inbred C57BL; Neuroprotective Agents--pharmacology; Neuroprotective Agents--toxicity; Oxidative Stress--drug effects; Oxidopamine--toxicity; Phosphorylation--drug effects; Protein Phosphatase 2--metabolism; Proto-Oncogene Proteins c-akt--metabolism; Proto-Oncogene Proteins c-bcl-2--metabolism; Protons; Superoxide Dismutase--metabolism
Other ID: NLM PMC3192034
PubMed Central ID: PMC3192034
PubMed ID: 22022363
Date Deposited: 10 Sep 2012 14:12
Last Modified: 05 Dec 2023 11:55


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