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

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.

• Authors: C Culmsee, Y Zhu, J Krieglstein, M P Mattson
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 21 Issue 4 Pg. 334-43 (Apr 2001) ISSN: 0271-678X [Print] United States
• PMID: 11323519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• Oligodeoxyribonucleotides, Antisense
• prostate apoptosis response-4 protein
• Caspases

Topics

• Animals
• Apoptosis (physiology)
• Apoptosis Regulatory Proteins
• Carrier Proteins (genetics, metabolism)
• Caspases (metabolism)
• Cells, Cultured
• Corpus Striatum (cytology)
• Hippocampus (cytology)
• Infarction, Middle Cerebral Artery (metabolism)
• Intracellular Signaling Peptides and Proteins
• Ischemic Attack, Transient (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (cytology, enzymology)
• Oligodeoxyribonucleotides, Antisense (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Reperfusion Injury (metabolism)
• Stroke (metabolism)