Back to Search
Start Over
Protein kinase C delta mediates cerebral reperfusion injury in vivo.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2004 Aug 04; Vol. 24 (31), pp. 6880-8. - Publication Year :
- 2004
-
Abstract
- 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 deltaPKC, deltaV1-1, we found that deltaPKC 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-conjugateddeltaV1-1 and by measuring inhibition of intracellular deltaPKC translocation, an indicator of deltaPKC activity. Delivery of deltaV1-1 decreased infarct size in an in vivo rat stroke model of transient middle cerebral artery occlusion. Importantly, deltaV1-1 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 deltaPKC in mediating apoptotic processes. We therefore determined whether deltaPKC inhibition altered apoptotic cell death or cell survival pathways in our models. We found that deltaV1-1 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 deltaPKC during reperfusion and suggest that deltaV1-1 delivery, even hours after commencement of reperfusion, may provide a therapeutic advantage after cerebral ischemia.
- Subjects :
- Animals
Animals, Newborn
Apoptosis
Disease Models, Animal
Gene Products, tat
Hippocampus
In Vitro Techniques
Infarction, Middle Cerebral Artery
Male
Neuroprotective Agents pharmacology
Protein Kinase C antagonists & inhibitors
Protein Kinase C-delta
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins
Reperfusion Injury prevention & control
Signal Transduction
Brain Ischemia physiopathology
Protein Kinase C physiology
Reperfusion Injury physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 24
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 15295022
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.4474-03.2004