Neuron-astrocyte interactions are critical for signalling, energy metabolism, extracellular ion and
glutamate homeostasis, volume regulation and neuroprotection in the CNS.
Glutamate uptake by astrocytes may prevent excitotoxic
glutamate elevation and determine neuronal survival. However, an excess of
glutamate can cause the death of astrocytes.
FK506, an inhibitor of
calcineurin, and an immunosuppressive drug, is neuroprotective in animal models of neurologic diseases, including focal and global ischaemia. In the present work, we demonstrate that a single injection of
FK506 60 min after a transient
middle cerebral artery occlusion (MCAo) significantly decreases the number of
terminal deoxynucleotidyl transferase nick-end labelling (TUNEL)-positive cells in the ischaemic cortex and striatum. Using 3-D confocal microscopy we found that, 24 h after MCAo, many TUNEL-positive cells in the ischaemic striatum and cortex are astrocytes. Furthermore, we demonstrate that exposure of cultured cortical astrocytes to 50-100 mM Glu for 24 h induces apoptotic alterations in nuclear morphology, DNA fragmentation, dissipation of mitochondrial transmembrane potential (DeltaPsi) and
caspase activation.
FK506 (1 muM) efficiently inhibits Glu-induced apoptosis of cultured astrocytes, DNA fragmentation and changes in mitochondrial DeltaPsi. Our findings suggest that modulation of
glutamate-induced astrocyte death early after reperfusion may be a novel mechanism of FK506-mediated neuroprotection in ischaemia.