Treatment with 6-hydroxydopamine significantly reduced the viability of cultured rat primary astrocytes, rat astrocytoma cell line C6, and human astrocytoma cell line U251. 6-Hydroxydopamine-treated astrocytes exhibited altered nuclear morphology, DNA fragmentation, and reduced intracellular esterase activity, which indicated apoptotic cell death. Astrocytes were protected by neutralization of 6-hydroxydopamine autooxidation products H(2)O(2), O(2)(*-), and (*)OH, but not by cell-derived or chemically generated anti-apoptotic free radical nitric oxide. Finally, 6-hydroxydopamine activated extracellular signal-regulated kinase in astrocytes and selective inhibitor of extracellular signal-regulated kinase activation partially prevented astrocyte death. Taken together, these data indicate that 6-hydroxydopamine-triggered oxidative stress induces extracellular signal-regulated kinase-dependent apoptotic death of astrocytes.