Cardiopulmonary arrest remains one of the leading causes of death and disability in the U.S.A. The chances of survival following cardiac arrest are poor, despite fast emergency responses and better techniques of defibrillation. Cardiac arrest with its consequent disruption of blood flow sets in motion a cascade of cellular derangements that result in brain damage. Neurological dysfunction after cardiac arrest results from a number of factors, including aberrant cerebral blood flow, free radical formation, release of excitatory amino acids, mitochondrial dysfunction and synaptic dysfunction. Based on our results from the previous funding period, our focus is on the interaction of Protein Kinase C delta with vascular and neuronal elements after cardiac arrest. Our central hypothesis is that cardiac arrest activates ? PKC in key elements of the neurovascular unit resulting in derangements in cerebral blood flow and synaptic balance. Our goal is to define the relationship between ? PKC, deranged cerebral blood flow and synaptic dysfunction after cardiac arrest in the hippocampus. To accomplish this, we will rely on the rat asphyxial model of cardiac arrest optimized in our laboratory during the previous funding period. We will bring to bear new technological approaches including in vivo two-photon microscopy of individual microvessels, in vitro tissue bath approaches to study blood vessels, and brain slice imaging and electrophysiology methods to directly evaluate the impact of cardiac arrest and manipulations of ? PKC on hippocampal pyramidal cells, interneurons, and microvessels. We propose to test this general hypothesis in the following 4 specific aims.
Specific Aim 1 : To determine mechanisms by which ? PKC modulates CBF in micro- and macro- vessels.
Specific Aim 2 : To determine the specific mechanisms by which ? PKC promotes deranged CBF after ACA.
Specific Aim 3 : To determine the specific mechanisms by which ? PKC deranges neurovascular coupling between hippocampal CA1 pyramidal cells, interneurons and cerebral microvessels after cardiac arrest.
Specific Aim 4 : To determine whether dV1-1 post-treatment improves cognitive deficits and long term histopathology in a rat model of asphyxial cardiac arrest.
Cardiopulmonary arrest remains one of the leading causes of death and disability in the USA and survival rates following cardiac arrest (CA) are poor, despite prompt emergency treatment and better resuscitation techniques. The goal of this application is to better understand the mechanisms of neuropathology following cardiac arrest and to develop novel therapies to ameliorate this neuropathology.
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