Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death by a mitochondrial inhibitor.
Intrastriatal injections of the mitochondrial toxins malonate and 3-nitropropionic acid produce selective cell death similar to that seen in transient ischemia and Huntington's disease. The extent of cell death can be attenuated by pharmacological or surgical blockade of cortical glutamatergic input. It is not known, however, if dopamine contributes to toxicity caused by inhibition of mitochondrial function. Exposure of primary striatal cultures to dopamine resulted in dose-dependent death of neurons. Addition of medium supplement containing free radical scavengers and antioxidants decreased neuronal loss. At high concentrations of the amine, cell death was predominantly apoptotic. Methyl malonate was used to inhibit activity of the mitochondrial respiratory chain. Neither methyl malonate (50 microM) nor dopamine (2.5 microM) caused significant toxicity when added individually to cultures, whereas simultaneous addition of both compounds killed 60% of neurons. Addition of antioxidants and free radical scavengers to the incubation medium prevented this cell death. Dopamine (up to 250 microM) did not alter the ATP/ADP ratio after a 6-h incubation. Methyl malonate, at 500 microM, reduced the ATP/ADP ratio by approximately 30% after 6 h; this decrease was not augmented by coincubation with 25 microM dopamine. Our results suggest that dopamine causes primarily apoptotic death of striatal neurons in culture without damaging cells by an early adverse action on oxidative phosphorylation. However, when combined with minimal inhibition of mitochondrial function, dopamine neurotoxicity is markedly enhanced.
McLaughlin
B A
BA
Institute of Neurological Sciences, University of Pennsylvania, Philadelphia, USA.
Nelson
D
D
Erecińska
M
M
Chesselet
M F
MF
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004247:DNA / Q000032:analysis; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D008314:Malonates / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009627:Nomifensine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013997:Time Factors; D014741:Video Recording
D000975:Antioxidants; D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D016166:Free Radical Scavengers; D008314:Malonates; D009627:Nomifensine; D000255:Adenosine Triphosphate; D004247:DNA; C005230:methyl malonate; D004298:Dopamine; D009638:Norepinephrine