Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.
Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.
Cadet
J L
JL
Molecular Neuropsychiatry Section, NIH/NIDA/IRP, Baltimore, Maryland 21224, USA.
Ordonez
S V
SV
Ordonez
J V
JV
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005434:Flow Cytometry; D008694:Methamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology*; D051381:Rats
D019253:Proto-Oncogene Proteins c-bcl-2; D008694:Methamphetamine