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

Calcineurin, a ubiquitous calcium-activated serine phosphatase, plays an im portant role in the signal transduction. We have previously reported that c yclosporin A (CsA) inhibits the growth and survival of the rat C6 glioma ce lls due to the inhibition of signaling pathway involving calcineurin and tr anscription factor nuclear factor of activated T cells (NFAT). In the prese nt study, we show that CsA affects the survival of reactive astrocyte cultu res derived from striatal trauma. Exposure of reactive astrocytes to doses of CsA > 50 mug/ml for 24-72 h produces morphological changes, including ce ll body shrinkage and loss of extensions, followed by cell death. This deat h was accompanied by apoptotic changes in nuclear morphology and DNA fragme ntation: as revealed by Hoechst 33258 and positive TUNEL staining. We demon strated the presence of calcineurin A subunit in reactive astrocytes and co rpus callosum (brain structure enriched in astrocytes) and an additional ca lcineurin-like protein occurring solely in reactive astrocytes. FK506, a ca lcineurin inhibitor unrelated to CsA, inhibits proliferation of astrocytes and induces death accompanied by apoptotic changes in nuclear morphology an d DNA fragmentation. Since calcineurin is a major target for both CsA and F K506, the results suggest that this phosphatase is involved in the regulati on of reactive astrocyte survival. (C) 2001 Elsevier Science Ltd. All right s reserved.