Protein kinase C δ mediates cerebral reperfusion injury In Vivo

Rachel Bright, Ami P. Raval, Jeffrey M. Dembner, Miguel A. Pérez-Pinzón, Gary K. Steinberg, Midori A. Yenari, Daria Mochly-Rosen

Research output: Contribution to journalArticle

158 Scopus citations

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 δPKC, δV1-1, we found that δPKC 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-conjugated δV1-1 and by measuring inhibition of intracellular δPKC translocation, an indicator of δPKC activity. Delivery of δV1-1 decreased infarct size in an in vivo rat stroke model of transient middle cerebral artery occlusion. Importantly, δV1-1 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 δPKC in mediating apoptotic processes. We therefore determined whether δPKC inhibition altered apoptotic cell death or cell survival pathways in our models. We found that δV1-1 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 δPKC during reperfusion and suggest that δV1-1 delivery, even hours after commencement of reperfusion, may provide a therapeutic advantage after cerebral ischemia.

Original languageEnglish (US)
Pages (from-to)6880-6888
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number31
DOIs
StatePublished - Aug 4 2004

Keywords

  • Hippocampus
  • Ischemia
  • Neuroprotection
  • OGD
  • Peptide inhibitor
  • PKC

ASJC Scopus subject areas

  • Neuroscience(all)

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