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

PLoS One. 2011;6(10):e24722. doi: 10.1371/journal.pone.0024722. Epub 2011 Oct 12.

Abstract

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 [(3)H] 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Protons
  • Methamphetamine
  • Oxidopamine
  • Superoxide Dismutase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Protein Phosphatase 2
  • Dopamine