 |
The Journal of Neuroscience, August 4, 2004, 24(31):6880-6888; doi:10.1523/JNEUROSCI.4474-03.2004
 Previous Article | Next Article 
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.
This article has been cited by other articles:
|
|
|
|
 
J. Kim, Y.-L. Choi, A. Vallentin, B. S. Hunrichs, M. K. Hellerstein, D. M. Peehl, and D. Mochly-Rosen
Centrosomal PKC{beta}II and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis
Cancer Res.,
August 15, 2008;
68(16):
6831 - 6839.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Qi and D. Mochly-Rosen
The PKC{delta} -Abl complex communicates ER stress to the mitochondria - an essential step in subsequent apoptosis
J. Cell Sci.,
March 15, 2008;
121(6):
804 - 813.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Sud, S. Wedgwood, and S. M. Black
Protein kinase C{delta} regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation
Am J Physiol Lung Cell Mol Physiol,
March 1, 2008;
294(3):
L582 - L591.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ansar and L. Edvinsson
Subtype Activation and Interaction of Protein Kinase C and Mitogen-Activated Protein Kinase Controlling Receptor Expression in Cerebral Arteries and Microvessels After Subarachnoid Hemorrhage
Stroke,
January 1, 2008;
39(1):
185 - 190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Y. H. Chan, A. Y. W. Chang, L.-L. Wang, C.-C. Ou, and S. H. H. Chan
Protein Kinase C-Dependent Mitochondrial Translocation of Proapoptotic Protein Bax on Activation of Inducible Nitric-Oxide Synthase in Rostral Ventrolateral Medulla Mediates Cardiovascular Depression during Experimental Endotoxemia
Mol. Pharmacol.,
April 1, 2007;
71(4):
1129 - 1139.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Ikeno, K. Inagaki, M. Rezaee, and D. Mochly-Rosen
Impaired perfusion after myocardial infarction is due to reperfusion-induced {delta}PKC-mediated myocardial damage
Cardiovasc Res,
March 1, 2007;
73(4):
699 - 709.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Brandman, M.-H. Disatnik, E. Churchill, and D. Mochly-Rosen
Peptides Derived from the C2 Domain of Protein Kinase C{epsilon} ({epsilon}PKC) Modulate {epsilon}PKC Activity and Identify Potential Protein-Protein Interaction Surfaces
J. Biol. Chem.,
February 9, 2007;
282(6):
4113 - 4123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vallentin and D. Mochly-Rosen
RBCK1, a Protein Kinase CbetaI (PKCbetaI)-interacting Protein, Regulates PKCbeta-dependent Function
J. Biol. Chem.,
January 19, 2007;
282(3):
1650 - 1657.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Kheifets, R. Bright, K. Inagaki, D. Schechtman, and D. Mochly-Rosen
Protein Kinase C {delta} ({delta}PKC)-Annexin V Interaction: A REQUIRED STEP IN {delta}PKC TRANSLOCATION AND FUNCTION
J. Biol. Chem.,
August 11, 2006;
281(32):
23218 - 23226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Greenberg
Another weapon against amyloid
PNAS,
May 23, 2006;
103(21):
7943 - 7944.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Zatta, H. Kin, G. Lee, N. Wang, R. Jiang, R. Lust, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, et al.
Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling
Cardiovasc Res,
May 1, 2006;
70(2):
315 - 324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Kostyak, J. C. Hunter, and D. H. Korzick
Acute PKC{delta} inhibition limits ischaemia-reperfusion injury in the aged rat heart: Role of GSK-3{beta}
Cardiovasc Res,
May 1, 2006;
70(2):
325 - 334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bright and D. Mochly-Rosen
The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury
Stroke,
December 1, 2005;
36(12):
2781 - 2790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Fleegal, S. Hom, L. K. Borg, and T. P. Davis
Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation
Am J Physiol Heart Circ Physiol,
November 1, 2005;
289(5):
H2012 - H2019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Lallemend, S. Hadjab, G. Hans, G. Moonen, P. P. Lefebvre, and B. Malgrange
Activation of protein kinase C{beta}I constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons
J. Cell Sci.,
October 1, 2005;
118(19):
4511 - 4525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bloch-Shilderman, T. Kadar, A. Levy, R. Sahar, I. Rabinovitz, and E. Gilat
Subcellular Alterations of Protein Kinase C Isozymes in the Rat Brain after Organophosphate Poisoning
J. Pharmacol. Exp. Ther.,
June 1, 2005;
313(3):
1082 - 1089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
