NF-κB as a common signaling pathway in ganglioside-induced autophagic cell death and activation of astrocytes

We have previously shown that gangliosides induce autophagic cell death of brain astrocytes. As gangliosides are also known to induce inflammatory activation of astrocytes, we hypothesized that a canonical inflammatory signaling pathway NF-kappa B might be involved in the ganglioside-induced astrocyte cell death and activation. Using cultured mouse astrocytes and C6 rat glioma cell line, we determined the role of NF-kappa B in autophagic cell death and nitric oxide (NO) production in astrocytes. Gangliosides induced iNOS/GFAP expression and NF-kappa B activation. IKK inhibitor SC-514 and NF-kappa B inhibitor PDTC reduced ganglioside-induced astrocyte activation and cell death. Moreover, inhibition of NF-kappa B pathway also attenuated autophagy of astrocytes. Rho subfamily of small G proteins antagonized the ganglioside-induced astrocyte cell death as well as activation pathways. Taken together, IKK/NF-kappa B may constitute one of the common signaling pathways in ganglioside-induced astrocyte activation and autophagic cell death, and may play an important role in the ganglioside intracellular signaling that regulates astrocyte physiology and pathology. (C) 2010 Elsevier B.V. All rights reserved.