Gangliosides activate cultured bat brain microglia

Microglia, brain resident macrophages, are activated in brain injuries and several neurodegenerative diseases. However, microglial activators that are produced in the brain are not yet defined. In this study, we showed that g angliosides, sialic acid-containing glycosphingolipids, could be a microgli al activator. Gangliosides induced production of nitric oxide (NO) and tumo r necrosis factor-alpha (TNF-alpha) and expression of cyclooxygenase-a (COX -2). The effect of gangliosides on NO release increased dose-dependently in the range of 10-100 mu g/ml; however, the effect decreased at concentratio ns higher than 200 mu g/ml. Specific types of gangliosides showed different ial effects on microglial activation. Similar to gangliosides, GT1b induced production of NO and TNF-alpha and expression of COX-2. However, GM1 and G D1a induced expression of COX-2 but had little effect on NO and TNF-alpha r elease. The effect of gangliosides and GT1b an NO release was reduced in th e presence of neuraminidase, which removes sialic acid residues from gangli osides and GT1b. Gangliosides activated extracellular signal-regulated kina se significantly but activated c-jun N-terminal kinase/stress-activated pro tein kinase and p38 relatively weakly. The inhibition of extracellular sign al-regulated kinase by PD98059 reduced NO release from both gangliosides- a nd GT1b-treated microglia whereas inhibition of p38 by SB203580 increased i t rather slightly. Gangliosides activated NF-kappa B, and N-acetyl cystein, an inhibitor of NF-kappa B, reduced NO release. These results suggest that gangliosides could be a microglial activator that functions via activation of mitogen-activated protein kinase and NF-kappa B.