DOPAMINE NEUROTOXICITY IN CORTICAL-NEURONS

Dopamine (DA), at concentrations greater than 100 mu M, has previously been demonstrated to be toxic to mesencephalic, striatal and dorsal r oot ganglion cell cultures. Pharmacological experiments suggest that D A also may play a role in the cortical neurotoxicity caused by systemi c 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 calce in and ethidium homodimer fluorescence as a marker for live an dead ce lls, respectively, we observed that a 24 h treatment with 10-100 mu M DA produced a concentration-dependent increase in the number of ethidi um homodimer-labelled cells. The cell death induced by 10 mu M DA was dramatically reduced by co-administration of either superoxide dismuta se and catalase or deferoxamine mesylate, an iron chelator. To verify this observation, the effects of 10 mu M DA on the release of cytoplas mic 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 rele ase, suggesting a protective role for DA uptake in this system. On the other hand, neither D-1 nor D-2 antagonists were able to prevent DA-i nduced LDH release. These data suggest that relatively low concentrati ons of DA can be injurious to cortical neurons through a mechanism tha t likely involves DA autooxidation and the formation of reactive oxyge n species such as superoxide anion and hydroxyl radical. This mechanis m may be important in the toxic effects of psychomotor stimulants such as amphetamine. However, the failure of DA receptor antagonists to af fect DA-induced injury argues that the effect of DA on cortical neuron s in culture does not model the toxic effect of phencyclidine and MK-8 01 observed in vivo. (C) 1997 Elsevier Science Ireland Ltd.