Cyclosporin A-sensitive signaling pathway involving calcineurin regulates survival of reactive astrocytes

Calcineurin, a ubiquitous calcium-activated serine phosphatase, plays an important role in the signal transduction. We have previously reported that cyclosporin A (CsA) inhibits the growth and survival of the rat C6 glioma cells due to the inhibition of signaling pathway involving calcineurin and transcription factor nuclear factor of activated T cells (NFAT). In the present study, we show that CsA affects the survival of reactive astrocyte cultures derived from striatal trauma. Exposure of reactive astrocytes to doses of CsA > 50 mug/ml for 24-72 h produces morphological changes, including cell body shrinkage and loss of extensions, followed by cell death. This death was accompanied by apoptotic changes in nuclear morphology and DNA fragmentation: as revealed by Hoechst 33258 and positive TUNEL staining. We demonstrated the presence of calcineurin A subunit in reactive astrocytes and corpus callosum (brain structure enriched in astrocytes) and an additional calcineurin-like protein occurring solely in reactive astrocytes. FK506, a calcineurin inhibitor unrelated to CsA, inhibits proliferation of astrocytes and induces death accompanied by apoptotic changes in nuclear morphology and DNA fragmentation. Since calcineurin is a major target for both CsA and FK506, the results suggest that this phosphatase is involved in the regulation of reactive astrocyte survival. (C) 2001 Elsevier Science Ltd. All rights reserved.