Abstract
Cerebral ischemia is known to induce cell death through hypoxia and oxidative stress following reperfusion. However, cell death can spread beyond the ischemic core when toxic glutamate levels act on NMDA receptors of surrounding regions. Levels of CXCL12, a chemokine primarily released from glia, reportedly elevate following ischemia. Acute activation of its receptor, CXCR4, appears to serve a neuroprotective function while prolonged activation results in cell death and this cell death was reported to be dependent on the combined release of calcium from intracellular stores as well as calcium influx through NMDARs. Calcium influx through NMDA receptor channels leads to activation of CaMKII, and it has also been shown that intracellular calcium can be sufficient to activate CaMKII. Thus, it is of interest to determine if cell death following CXCL12 application is mediated by CaMKII; and further, if exposure to CXCL12 primes neurons for glutamate-induced toxicity thus increasing cell death. Here, it was confirmed that acute (30 min) delivery of CXCL12 is not detrimental, while sustained activation (3 hour) resulted in a significant increase in cell death compared to controls. In addition, both acute and sustained CXCL12 exposure induced translocation of CaMKII to synapses. Delivery of a strong excitatory stimulus (500 μM glu + 10 μM gly) following either acute or sustained CXCL12 application appeared to elevate susceptibility to glutamate-induced cell death. Interestingly, pre-exposure to CXCL12 also induced cell death following delivery of a more physiologically relevant concentration of glutamate (100 μM glu + 10 μM gly). Peptide inhibitors that act to block CaM or ATP binding to CaMKII both appeared to reduce CXCL12-induced increases in cell death. These v results suggest that both acute and sustained CXCR4 activation increase neuron susceptibility to excitotoxicity and this priming is at least partially mediated by CaMKII.
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