Signal cascade of glial apoptosis and its protection

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The present study was carried out to clarify the mechanisms of cell death in cultured astrocytes, microglia and neurons. Incubation of cultured astrocytes in Ca^<2+>-containing medium after exposure to Ca^<2+>-free medium causes an increase in intracellular Ca^<2+> concentration followed by,delayed cell death. This injury is considered to be an in vitro model of ischaemia/reperfusion injury. This review summarizes our current studies on the mechanisms underlying the Ca^<2+>-mediated injury of cultured astrocytes and, target molecules, for drugs to prevent the reperfusion injury. Ca^<2+> reperfusion injury of astrocytes appears to be mediated by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species, calcineurin, caspase-3, and NF-κB are involved in the Ca^<2+> reperfusion injury. Several neuroprotective drugs including NGF, T-588, idebenone, and ibudilast prevent astrocyte apoptosis in the reperfusion injury models using Ca^<2+> depletion or hydrogen peroxide. The protective effects of these drugs are, mediated by phosphatidylinositol-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase, nerve growth factor production, and cyclic GMP-dependent protein kinase. The analysis on the mechanism for the cyclic GMP effect indicates that the mitochondrial permeability transition pore plays a key role in, apoptotic events of cultured astrocytes