The toxicity of 6-hydroxydopamine on PC12 and P19 cells.
Considerable evidence implicates the involvement of mitochondrial dysfunction in neurodegenerative diseases. 6OHDA is a mitochondrial complex I inhibitor which is frequently used to model Parkinson's disease-like cell loss. We investigated the cell death pathways triggered by 6OHDA in PC12 and P19 cells with a view to shedding light on the molecular basis of Parkinson's disease. We found that 6OHDA triggered mostly necrosis and less than 5% apoptosis in PC12 cells, whereas 6OHDA-induced death in P19 cells was apoptotic. While desipramine, a dopamine uptake blocker, attenuated 6OHDA-induced apoptosis in PC12 cells, this compound had no effect on the large scale necrotic death. Furthermore, desipramine failed to reduce apoptosis in 6OHDA-treated P19 cells, suggesting that the mechanism of 6OHDA toxicity does not require uptake via the dopamine transporter. As cell death triggered by 6OHDA was not blocked by free radical scavengers or NMDA receptor antagonists, a non-specific extracellular mechanism may be involved.
Woodgate
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A
Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand.
MacGibbon
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G
Walton
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M
Dragunow
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D006690:Bisbenzimidazole; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008550:Melatonin / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D016716:PC12 Cells; D010302:Parkinson Disease, Secondary / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D013565:Sympatholytics / Q000633:toxicity*; D014212:Tretinoin / Q000494:pharmacology; D014316:Tritium
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D013565:Sympatholytics; D014316:Tritium; D001312:Aurintricarboxylic Acid; D014212:Tretinoin; D016627:Oxidopamine; D008550:Melatonin; D006690:Bisbenzimidazole; D003891:Desipramine; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine