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The Journal of Neuroscience, August 4, 2004, 24(31):6880-6888; doi:10.1523/JNEUROSCI.4474-03.2004
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Neurobiology of Disease
Protein Kinase C  Mediates Cerebral Reperfusion Injury In Vivo
Rachel Bright,1
Ami P. Raval,5
Jeffrey M. Dembner,2
Miguel A. Pérez-Pinzón,5
Gary K. Steinberg,2,3,4
Midori A. Yenari,2,3,4 and
Daria Mochly-Rosen1
Departments of 1Molecular Pharmacology, 2Neurosurgery, and 3Neurology and Neurological Sciences, 4Stanford Stroke Center, Stanford University School of Medicine, Stanford, California 94305, and 5Cerebral Vascular Disease Research Center, Department of Neurology and Neuroscience, University of Miami School of Medicine, Miami, Florida 33101
Protein kinase C (PKC) has been implicated in mediating ischemic and reperfusion damage in multiple organs. However, conflicting reports exist on the role of individual PKC isozymes in cerebral ischemic injury. Using a peptide inhibitor selective for  PKC, V1-1, we found that PKC inhibition reduced cellular injury in a rat hippocampal slice model of cerebral ischemia [oxygen-glucose deprivation (OGD)] when present both during OGD and for the first 3 hr of reperfusion. We next demonstrated peptide delivery to the brain parenchyma after in vivo delivery by detecting biotin-conjugatedV1-1 and by measuring inhibition of intracellular PKC translocation, an indicator of PKC activity. Delivery of V1-1 decreased infarct size in an in vivo rat stroke model of transient middle cerebral artery occlusion. Importantly, V1-1 had no effect when delivered immediately before ischemia. However, delivery at the onset, at 1 hr, or at 6 hr of reperfusion reduced injury by 68, 47, and 58%, respectively. Previous work has implicated PKC in mediating apoptotic processes. We therefore determined whether PKC inhibition altered apoptotic cell death or cell survival pathways in our models. We found that V1-1 reduced numbers of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells, indicating decreased apoptosis, increased levels of phospho-Akt, a kinase involved in cell survival pathways, and inhibited BAD (Bcl-2-associated death protein) protein translocation from the cell cytosol to the membrane, indicating inhibition of proapoptotic signaling. These data support a deleterious role for PKC during reperfusion and suggest that V1-1 delivery, even hours after commencement of reperfusion, may provide a therapeutic advantage after cerebral ischemia.
Key words: ischemia; OGD; neuroprotection; hippocampus; peptide inhibitor; PKC
Received June 27, 2003;
revised June 19, 2004;
accepted June 19, 2004.
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|
|
|
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|
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[PDF]
|
|
|
|
|
|
|
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|
|
|
|
|
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103(21):
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|
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|
|
|
|
|
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70(2):
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|
|
|
|
|
|
|
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May 1, 2006;
70(2):
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[Full Text]
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|
|
|
|
|
|
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|
|
|
|
|
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