Astrocytes, the most abundant glial cell type in the brain, are considered to have physiological and pathological roles in neuronal activities. We found that reperfusion of cultured astrocytes after Ca
2+ depletion causes Ca
2+ overload followed by delayed cell death and the Na
+-Ca
2+ exchanger in the reverse mode is responsible for this Ca
2+-mediated cell injury (Ca
2+ paradox injury). The Ca
2+ paradox injury of cultured astrocytes is considered to be an in vitro model of ischemia/reperfusion injury, since a similar paradoxical change in extracellular Ca
2+ concentration is reported in ischemic brain tissue. This review summarizes the mechanisms underlying the Ca
2+-mediated injury of astrocytes and the protective effects of drugs against Ca
2+ reperfusion injury. This study shows that Ca
2+ reperfusion injury of astrocytes is accompanied by apoptosis as evidenced by DNA fragmentation and nuclear condensation. Calpain, reactive oxygen species, calcineurin, caspase-3, and NF-κB are involved in Ca
2+ reperfusion-induced delayed apoptosis of astrocytes. Several drugs including CV-2619, T-588 and ibudilast protect astrocytes against the delayed apoptosis. CV-2619 prevents astrocytes from the delayed apoptosis by production of nerve growth factor, resulting in an activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 (PI3) kinase signal pathways. The protective effect of T-588 is mainly mediated by an activation of MAP/ERK signal cascade. Moreover, ibudilast prevents the Ca
2+ reperfusion-induced delayed apoptosis of astrocytes via cyclic GMP signaling pathway. Further studies in this system will contribute to the development of new drugs that attenuate ischemia/reperfusion injury via modulation of astrocytes.
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