RESUMO
OBJECTIVE: Recent studies on cerebral ischemia in the rat have demonstrated that administration of interleukin-1 receptor antagonist (IL-1ra) markedly reduces the volumes of infarcts which are associated with N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. These observations suggested that endogenous interleukin-1 (IL-1) may be involved in the mediation of excitotoxic neuronal injury following ischemia. METHOD: In the present studies, we examined the role of interleukin-1beta (IL-1beta) in NMDA-related and microglia-induced excitotoxicity in cocultures of mixed neurons and microglia. RESULTS: Our observations in these mixed cultures indicated that addition of IL-1beta exaggerated NMDA and glutamate-evoked hippocampal neuron death. Addition of microglia, activated by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), to cocultures of cortical neurons and glia induced significantly greater neurotoxicity when compared with cocultures of cortical neurons and untreated microglia. This neurotoxicity did not require that activated glia be in cell-to-cell contact with neurons. Addition of either IL-1ra or the NMDA receptor antagonist MK-801 to cocultures of cortical neurons and activated glia partially reversed the neuronal damage mediated by activated microglia. Finally, IL-1beta concentrations in the supernatant of cocultures of cortical neurons and microglia treated by LPS and IFN-gamma were markedly increased when compared with coculture of neurons with untreated microglia. CONCLUSION: These results suggest that both the NMDA receptor and the IL-1 receptor are involved in microglia-mediated neurotoxicity.
