Paraquat induced activation of transcription factor AP-1 and apoptosis in PC12 cells.
Drugs and certain environmental toxins may be responsible for the pathogenesis of Parkinson's disease. We have used paraquat as a model toxin for this study since paraquat has been shown to make its way to the nerve terminals and cause cell death of dopamine neurons by oxidative injury. We have shown by the electrophoretic mobility shift assay that paraquat, together with low concentrations of chelated iron (Fe++/DETAPAC), induced the activation of transcription factor AP-1 binding activity to DNA. Under similar conditions we also found by both a DNA laddering assay procedure and by terminal deoxynucleotidyl transferase assay (TUNEL assay) that paraquat also induces apoptotic cell death. Interestingly, both apoptotic cell death and AP-1/DNA binding activity induced by paraquat were blocked by cyclohexamide and genistein, indicating that both the AP-1/DNA binding activation and apoptosis induced by paraquat are closely related. Moreover, cells were also protected from paraquat toxicity in the presence of antioxidant defense enzymes SOD and catalase. The results support the hypothesis that oxidative stress may be contributing to the apoptotic cell death of dopaminergic neurons, leading to the manifestation of Parkinson's disease. Since paraquat was an important herbicide in the mid 20th Century, our results have the important implication that exposure to environmental toxins such as paraquat may induce Parkinson's disease.
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Department of Pharmacology, University of Missouri, Columbia 65212, USA.
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D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006540:Herbicides; D011500:Protein Synthesis Inhibitors; D018808:Transcription Factor AP-1; D004247:DNA; D003513:Cycloheximide; D019833:Genistein; D010269:Paraquat