To promote functional recovery after CNS injuries, it is crucial to develop strategies that enhance both neuronal survival and regeneration. Here, we report that caspase-6 is upregulated in injured retinal ganglion cells and that its inhibition promotes both survival and regeneration in these adult CNS neurons. Treatment of rat retinal whole mounts with Z-VEID-FMK, a selective inhibitor of caspase-6, enhanced ganglion cell survival. Moreover, retinal explants treated with this drug extended neurites on myelin. We also show that caspase-6 inhibition resulted in improved ganglion cell survival and robust axonal regeneration following optic nerve injury in adult rats. The effects of Z-VEID-FMK were similar to other caspase inhibitory peptides including Z-LEHD-FMK and Z-VAD-FMK. In searching for downstream effectors for caspase-6, we identified caspase-8, whose expression pattern resembled that of caspase-6 in the injured eye. We then showed that caspase-8 is activated downstream of caspase-6 in the injured adult retina. Furthermore, we investigated the role of caspase-8 in RGC apoptosis and regenerative failure both in vitro and in vivo. We observed that caspase-8 inhibition by Z-IETD-FMK promoted survival and regeneration to an extent similar to that obtained with caspase-6 inhibition. Our results indicate that caspase-6 and caspase-8 are components of a cellular pathway that prevents neuronal survival and regeneration in the adult mammalian CNS.
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 (DY) and caspase activation. FK506 (1 lM) efficiently inhibits Glu-induced apoptosis of cultured astrocytes, DNA fragmentation and changes in mitochondrial DY. Our findings suggest that modulation of glutamate-induced astrocyte death early after reperfusion may be a novel mechanism of FK506-mediated neuroprotection in ischaemia. Keywords: apoptosis, astrocyte death, FK506, glutamate, ischaemia, mitochondria. Astrocytes provide metabolic support to neurons, produce many trophic factors, and participate in detection, propagation and modulation of excitatory synaptic signals (Chen and Swanson 2003;Privat 2003). Brain damage in ischaemia comprises distinct pathological events, including excitotoxicity, neuronal death, activation of microglia, and reactive gliosis (Dirnagl et al. 1999). Massive release of glutamate (Glu), leading to excitotoxicity, plays a major role in neuronal death. Glutamate uptake by astrocytes may prevent excitotoxic Glu elevations and support neuronal survival in the ischaemic penumbra. Astrocytes might have important tissue-protective functions after CNS injury and ablation of glial scar-forming astrocytes in transgenic animals worsens neuronal injury (Bush et al. 1999;Faulkner et al. 2004). However, some studies demonstrated that astrocytic Glu transporters fail to quickly reduce high concentrations of Glu under pathological conditions and activated astrocytes have a decreased capacity for Glu to glutamine conversion (Ahlemeyer et al. 2002;Swanson et al. 2004). Moreover, under ischaemic conditions, activated astrocytes produce proinflammatory cytokines and toxic factors such as nitric oxide, reactive oxygen species, and form a 'glial scar', which blocks expansion of the injury but inhibits regeneration (Ridet et al. 1997;Perez-Capote et al. 2004;Dirnagl et al. 2005). It suggests that astrocytes may differentially influence neuronal survi...
SummaryVPS10P domain receptors emerge as central regulators of intracellular protein sorting in neurons with relevance for various brain pathologies. Here, we identified a role for the family member SorCS2 in protection of neurons from oxidative stress and epilepsy-induced cell death. We show that SorCS2 acts as sorting receptor that sustains cell surface expression of the neuronal amino acid transporter EAAT3 to facilitate import of cysteine, required for synthesis of the reactive oxygen species scavenger glutathione. Lack of SorCS2 causes depletion of EAAT3 from the plasma membrane and impairs neuronal cysteine uptake. As a consequence, SorCS2-deficient mice exhibit oxidative brain damage that coincides with enhanced neuronal cell death and increased mortality during epilepsy. Our findings highlight a protective role for SorCS2 in neuronal stress response and provide a possible explanation for upregulation of this receptor seen in surviving neurons of the human epileptic brain.
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