title: Dopamine neurotoxicity in cortical neurons.
abstract: Dopamine (DA), at concentrations greater than 100 microM, has previously been demonstrated to be toxic to mesencephalic, striatal and dorsal root ganglion cell cultures. Pharmacological experiments suggest that DA also may play a role in the cortical neurotoxicity caused by systemic administration of N-methyl-D-aspartate receptor antagonists such as phencyclidine and MK-801. In this study, the potential toxicity of DA in primary cortical cell cultures was determined in vitro. Using calcein and ethidium homodimer fluorescence as a marker for live and dead cells, respectively, we observed that a 24 h treatment with 10-100 microM DA produced a concentration-dependent increase in the number of ethidium homodimer-labelled cells. The cell death induced by 10 microM DA was dramatically reduced by co-administration of either superoxide dismutase and catalase or deferoxamine mesylate, an iron chelator. To verify this observation, the effects of 10 microM DA on the release of cytoplasmic lactate dehydrogenase (LDH) was measured. DA increased LDH release in a manner that was inhibited by both superoxide dismutase/catalase and deferoxamine. Nomifensine potentiated the effect of DA on LDH release, suggesting a protective role for DA uptake in this system. On the other hand, neither D1 nor D2 antagonists were able to prevent DA-induced LDH release. These data suggest that relatively low concentrations of DA can be injurious to cortical neurons through a mechanism that likely involves DA autooxidation and the formation of reactive oxygen species such as superoxide anion and hydroxyl radical. This mechanism may be important in the toxic effects of psychomotor stimulants such as amphetamine. However, the failure of DA receptor antagonists to affect DA-induced injury argues that the effect of DA on cortical neurons in culture does not model the toxic effect of phencyclidine and MK-801 observed in vivo.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
authors.forename: S
authors.initials: S
authors.lastname: Alagarsamy
authors.forename: M
authors.initials: M
authors.lastname: Phillips
authors.forename: T
authors.initials: T
authors.lastname: Pappas
authors.forename: K M
authors.initials: KM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology; D018929:Cell Culture Techniques; D016923:Cell Death; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009627:Nomifensine / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009627:Nomifensine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D010622:Phencyclidine; D004298:Dopamine