Evidence for the involvement of Par-4 in ischemic neuron cell death

After a stroke many neurons in the ischemic brain tissue die by a process c alled apoptosis, a form of cell death that may be preventable. The specific molecular cascades that mediate ischemic neuronal death are not well under stood. The authors recently identified prostate apoptosis response-3 (Par-4 ) as a protein that participates in the death of cultured hippocampal neuro ns induced by trophic factor withdrawal and exposure to glutamate. Here, th e authors show that Par-4 levels increase in vulnerable populations of hipp ocampal and striatal neurons in rats after transient forebrain ischemia; Pa r-4 levels increased within 6 hours of reperfusion and remained elevated in neurons undergoing apoptosis 3 days later. After transient focal ischemia in mice, Par-4 levels were increased 6 to 12 hours after reperfusion in the infarcted cortex and the striatum, and activation of caspase-8 occurred wi th a similar time course. Par-4 immunoreactivity was localized predominantl y in cortical neurons at the border of the infarct area. A Par-4 antisense oligonucleotide protected cultured hippocampal neurons against apoptosis in duced by chemical hypoxia and significantly reduced focal ischemic damage i n mice. The current data suggest that early up-regulation of Par-4 plays a pivotal role in ischemic neuronal death in animal models of stroke and card iac arrest.