Metallothionein provides zinc-mediated protective effects against methamphetamine toxicity in SK-N-SH cells.
Methamphetamine (METH) is a drug of abuse and neurotoxin that induces Parkinson's-like pathology after chronic usage by targeting dopaminergic neurons. Elucidation of the intracellular mechanisms that underlie METH-induced dopaminergic neuron toxicity may help in understanding the mechanism by which neurons die in Parkinson's disease. In the present study, we examined the role of reactive oxygen species (ROS) in the METH-induced death of human dopaminergic SK-N-SH cells and further assessed the neuroprotective effects of zinc and metallothionein (MT) against METH-induced toxicity in culture. METH significantly increased the production of reactive oxygen species, decreased intracellular ATP levels and reduced the cell viability. Pre-treatment with zinc markedly prevented the loss of cell viability caused by METH treatment. Zinc pre-treatment mainly increased the expression of metallothionein and prevented the generation of reactive oxygen species and ATP depletion caused by METH. Chelation of zinc by CaEDTA caused a significant decrease in MT expression and loss of protective effects of MT against METH toxicity. These results suggest that zinc-induced MT expression protects dopaminergic neurons via preventing the accumulation of toxic reactive oxygen species and halting the decrease in ATP levels. Furthermore, MT may prevent the loss of mitochondrial functions caused by neurotoxins. In conclusion, our study suggests that MT, a potent scavenger of free radicals is neuroprotective against dopaminergic toxicity in conditions such as drug of abuse and in Parkinson's disease.
Ajjimaporn
Amornpan
A
Department of Pharmacology, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
Swinscoe
John
J
Shavali
Shaik
S
Govitrapong
Piyarat
P
Ebadi
Manuchair
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008668:Metallothionein / Q000494:pharmacology*; D008694:Methamphetamine / Q000633:toxicity*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017967:Zinc Compounds / Q000494:pharmacology*
D002614:Chelating Agents; D002712:Chlorides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; D008694:Methamphetamine; C016837:zinc chloride; D000255:Adenosine Triphosphate; D008668:Metallothionein; D004298:Dopamine