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Evidence for the involvement of Par-4 in ischemic neuron cell death
C Culmsee1, Y Zhu, J Krieglstein
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, USA.
Abstract:
After a stroke many neurons in the ischemic brain tissue die by a process called apoptosis, a form of cell death that may be preventable. The specific molecular cascades that mediate ischemic neuronal death are not well understood. The authors recently identified prostate apoptosis response-4 (Par-4) as a protein that participates in the death of cultured hippocampal neurons induced by trophic factor withdrawal and exposure to glutamate. Here, the authors show that Par-4 levels increase in vulnerable populations of hippocampal and striatal neurons in rats after transient forebrain ischemia; Par-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 with a similar time course. Par-4 immunoreactivity was localized predominantly in cortical neurons at the border of the infarct area. A Par-4 antisense oligonucleotide protected cultured hippocampal neurons against apoptosis induced by chemical hypoxia and significantly reduced focal ischemic damage in 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 cardiac arrest.
Insights
Prostate apoptosis response-4 (Par-4) protein levels rise in brain cells after stroke, contributing to neuron death. Inhibiting Par-4 shows promise in protecting brain cells from ischemic injury in animal models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Ischemic stroke causes neuronal death via apoptosis, a process not fully understood.
- Prostate apoptosis response-4 (Par-4) was previously identified as a protein involved in neuronal apoptosis.
- The role of Par-4 in stroke-induced neuronal death requires further investigation.
Purpose of the Study:
- To investigate the role of Par-4 in neuronal death following ischemic events in animal models.
- To determine if Par-4 up-regulation correlates with apoptosis in ischemic brain tissue.
- To evaluate the therapeutic potential of targeting Par-4 in stroke models.
Main Methods:
- Assessed Par-4 protein levels in rat hippocampal and striatal neurons after transient forebrain ischemia.
- Examined Par-4 and caspase-8 activation in mouse cortical and striatal neurons following focal ischemia.
- Utilized Par-4 antisense oligonucleotide to assess its neuroprotective effects in vitro and in vivo.
Main Results:
- Par-4 levels significantly increased in vulnerable neurons within hours of reperfusion and persisted during apoptosis.
- Par-4 up-regulation and caspase-8 activation followed a similar time course in focal ischemia models.
- Par-4 inhibition protected cultured neurons from hypoxia-induced apoptosis and reduced brain damage in mice.
Conclusions:
- Early up-regulation of Par-4 is a key factor in ischemic neuronal death in stroke and cardiac arrest models.
- Par-4 represents a potential therapeutic target for mitigating stroke-related brain injury.
- Further research into Par-4's molecular mechanisms could lead to novel neuroprotective strategies.