Derangements of post-ischemic cerebral blood flow by protein kinase C delta

Abstract

Cerebral ischemia causes blood flow derangements characterized by hyperemia (increased cerebral blood flow, CBF) and subsequent hypoperfusion (decreased CBF). We previously demonstrated that protein kinase C delta (δPKC) plays an important role in hippocampal neuronal death after ischemia. However, whether part of this protection is due to the role of δPKC on CBF following cerebral ischemia remains poorly understood. We hypothesized that δPKC exacerbates hyperemia and subsequent hypoperfusion resulting in CBF derangements following ischemia. Sprague-Dawley (SD) rats pretreated with a δPKC specific inhibitor (δV1-1, 0.5 mg/kg) exhibited attenuation of hyperemia and latent hypoperfusion characterized by vasoconstriction followed by vasodilation of microvessels after 2-vessel occlusion plus hypotension measured by 2-photon microscopy. In an asphyxial cardiac arrest model (ACA), SD rats treated with δV1-1 (pre-and post-ischemia) exhibited improved perfusion after 24 hrs and less hippocampal CA1 neuronal death 7 days after ACA. These results suggest possible therapeutic potential of δPKC in modulating CBF and neuronal damage after cerebral ischemia. KeywordsProtein Kinase C Delta; Asphyxial Cardiac Arrest; Neuroprotection; Two-vessel Occlusion; Twophoton Microscopy; Cerebral Ischemia Cerebral ischemia is defined by little or no-blood flow in cerebral circulation characterized by low oxygen, glucose, and accumulation of metabolic products (Hossmann, 1997). A form of global cerebral ischemia (i.e. cardiac arrest), which affects whole-brain vascular dynamics, promotes neuronal cell death in many brain regions including the hippocampus Dave et al., 2006). It is well accepted that reperfusion after cerebral ischemia may substantially cause increased injury characterized by two phases: rapid hyperemia (increased blood flow) and delayed hypoperfusion (decreased blood flow) (Watson and Ginsberg, 1989;Choi, 1993). These derangements of cerebral blood flow (CBF) have been implicated in injury after global cerebral ischemia (Hosomi et al., 2007). Upon reperfusion, hyperemia and © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.Corresponding author: Miguel A. Perez-Pinzon, Ph.D., Department of Neurology, D4-5, University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101, Phone: (305) Fax: (305) 243-5830, perezpinzon@miami.edu. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure/Conflict of Interest:The authors have no conflict of interest in this manuscript. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 December 1. Publi...

Protein Kinase C Delta Modulates Endothelial Nitric Oxide Synthase after Cardiac Arrest

“…1,4 We previously showed that pretreatment of dV1-1 before ACA can enhance perfusion 24 hours after ischemia, resulting in improved neuronal survival in the hippocampal CA1 and cortex regions in our rat model of ACA.…”

“…The objective (from TPLSM) or probe (from LDF) was placed 1 mm lateral to the bregma as published earlier. 1,27 These two techniques are realtime CBF measurements to determine the effects of PKCd. We used L-arg, SNP, and NLA to define the relationship of PKCd and NOS machinery.…”

“…5 It is thought that the inhibition of PKCd (via dV1-1) can have beneficial effects against ischemia such as attenuation of hyperemia and hypoperfusion in models of global ischemia 1 and vascular protection against endothelial vascular dysfunction via modulation of eNOS. 5 In addition, degradation of PKCd during reperfusion improves physiologic outcome in the myocardial infarction 29 model altogether suggesting that ischemia causes activation/translocation of PKCd whereas inhibition or attenuation of PKCd can improve physiologic outcomes, as it relates to neuronal protection and/or revival of CBF.…”

“…The skull is thin enough for visualization of blood vessels via TPLSM when it is approximately half the thickness of the skull or approximately 0.5 mm. 1,6 Two-photon Laser Scanning Microscopy After thinning the skull, the rat was placed on a TPLSM (Lasersharp2000, Bio-Rad, Hercules, CA, USA). pH, mean arterial blood pressure, pCO 2 , pO 2 , glucose, rectal, and head temperatures were constantly monitored throughout the experiment.…”

“…Global cerebral ischemia (via ACA) causes derangement of cerebral blood flow (CBF) responsible for neuronal cell death in the CA1 region of the hippocampus as well as the cortex. 1 Owing to the overall decrease in CBF after ischemia, neuronal cell death 1 can occur in major regions of the brain responsible for learning, memory, and cognitive function. 2 It is thought that during global ischemia, PKCd (a novel PKC) levels are elevated causing PKCd to translocate to the nucleus (activation) resulting in cellular damage.…”