BID Mediates Neuronal Cell Death after Oxygen/Glucose Deprivation and Focal Cerebral Ischemia

Mitochondria and cytochrome c release play a role in the death of neurons and glia after cerebral ischemia. In the present study, we investigated whether BID, a proapoptotic promoter of cytochrome c release and caspase 8 substrate, was expressed in brain, activated after an ischemic insult in vivo a...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2001-12, Vol.98 (26), p.15318-15323
Main Authors: Plesnila, Nikolaus, Zinkel, Sandra, Le, Dean A., Amin-Hanjani, Sepideh, Wu, Yonqin, Qiu, Jianhua, Chiarugi, Alberto, Thomas, Sunu S., Kohane, Daniel S., Korsmeyer, Stanley J., Moskowitz, Michael A.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - physiology
B lymphocytes
BH3 Interacting Domain Death Agonist Protein
Bid protein
Biological Sciences
Brain
Brain ischemia
Brain Ischemia - pathology
Carrier Proteins - genetics
Carrier Proteins - physiology
Cell culture techniques
Cell death
Cells
Cultured cells
Cytochromes
Glucose
Glucose - metabolism
Ischemia
Mice
Mice, Transgenic
Neurons
Neurons - cytology
Oxygen
Oxygen - metabolism
Phenotype
Studies
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Summary:Mitochondria and cytochrome c release play a role in the death of neurons and glia after cerebral ischemia. In the present study, we investigated whether BID, a proapoptotic promoter of cytochrome c release and caspase 8 substrate, was expressed in brain, activated after an ischemic insult in vivo and in vitro, and contributed to ischemic cell death. We detected BID in the cytosol of mouse brain and primary cultured mouse neurons and demonstrated, by using recombinant caspase 8, that neuronal BID also is a caspase 8 substrate. After 2 h of oxygen/glucose deprivation, BID cleavage was detected in neurons concurrent with caspase 8 activation but before caspase 3 cleavage. Bid-/-neurons were resistant to death after oxygen/glucose deprivation, and caspase 3 cleavage was significantly reduced; however, caspase 8 cleavage did not differ from wild type. In vivo, BID was cleaved 4 h after transient middle cerebral artery occlusion. Infarct volumes and cytochrome c release also were less in Bid-/-mice (-67% and -41%, respectively) after mild focal ischemia. These findings suggest that BID and the mitochondrial-amplification pathway promoting caspase activation contributes importantly to neuronal cell death after ischemic insult.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.261323298