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Previously we reported that endotoxin-dependent induction of tumor necrosis factor alpha (TNFexpression in microglia was significantly suppressed by the superoxide anion scavenger N-acetyl cysteine (NAC), and that microglia induced TNF in response to a superoxide anion donor 3-(4-morpholinyl)sydnonimine (SIN-1) in vitro. Those findings strongly suggested that superoxide anion is associated with the induction of TNF in microglia. However, whether TNF is actually induced in microglia in vivo remains to be determined. In the present study, we confirmed the ability of microglia to induce TNF in vitro and examined the effects of SIN-1 on microglial induction of TNF in vivo. The accumulation of SIN-1 solution in rat cerebral cortex led to the induction of TNF on the ipsilateral, but not the contralateral side. The levels of TNF in the ipsilateral cortex peaked at 6-12 h post-accumulation. Immunohistochemical study revealed that anti-TNF antibody-positive cells in the SIN-1-injected region were mainly anti-ionized Ca 2+ binding adapter molecule-1 (Iba-1) antibody-positive, suggesting that microglia are a major cell type for inducing TNF. On the other hand, interleukin 1beta (IL-1) and IL-6 were not detected in the SIN-1-injected cortex. Together, these results indicate that microglia induced TNF in vivo in response to superoxide anion.