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Macrophage‐induced cytotoxicity of N‐methyl‐D‐aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines

The co‐localization of activated macrophages and damaged neurons observed in brain injury and degenerative brain diseases may hint to macrophage‐induced neuronal cytotoxicity. Recently, macrophages have been found to secrete neurotoxic molecules such as radical oxygen intermediates and glutamate, the latter interacting with N‐methyl‐D‐aspartate (NMDA) receptors. As shown in the present study, brain macrophages termed microglial cells co‐cultured with differentiated cerebellar neurons excert potent neurotoxic effects. Neurotoxicity is unlikely to be due to cytokines since tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6 and interferon (IFN)‐α/IFN‐β/IFN‐γ had no such effects. In contrast, when treating neurons with H2O2 or oxygen radical‐generating systems cytotoxicity was induced. Furthermore, microglia were found to produce O  2− and H2O2 when triggered with phorbol 12‐myristate 13‐acetate. However, in co‐cultures of neurons and microglia, oxygen‐radical scavengers catalase and superoxide dismutase, failed to protect neurons from microglia‐induced killing. Moreover, when using undifferentiated neurons which are susceptible to H2O2 but not to NMDA receptor‐dependent killing, microglia did not destroy the neurons. Thus, the amount of reactive oxygen intermediates produced by microglia in co‐culture do not reach the critical concentrations required for neurotoxicity. As dibenzocyclohepteneimide, an antagonist to NMDA receptors neutralized neurotoxicity in microglia‐neuronal co‐cultures, excitatory amino acids released by microglia are suggested to compose the major determinant of neurotoxicity.