Stroke is a leading cause of death and disability. At the present time, there are no effective therapeutic methods that can be used once a stroke has occurred that have been shown to ameliorate the damaging effects of the stroke. In addition, there are no predict eventual survival or residual neurological deficit. In order to rectify this situation it is not sufficient to simply screen potential pharmacologic agents, regardless of theoretical justification. What is needed is to study and understand the major cytotoxic cellular mechanisms that are initiated during and shortly after stroke. This project is designed to investigate the possibility that one of the cytotoxic mechanism includes the activation of the sodium/proton exchange transporter during the early period after reperfusion following stroke, resulting in an intracellular alkaline shift and producing and increased metabolic stress due to the volume changes caused by the accompanying intracellular influx of water. Our primary specific aim is to determine the time cause of the changes in brain intracellular pH after 10 minutes of reversible total cerebral ischemia in the rat. Cerebral intracellular pH will be determined by spectrophotometric measurements of the vital dye and pH indicator, neutral red, in vivo and in tissue frozen in situ. The method allows the simultaneous microregional determination of other metabolically significant substances in the the same tissue. Thus, we will be able to study the cellular reactions which result in acidification during ischemia, and those which are responsible for recovery from intracellular acidosis. A secondary aim involves the study of the cellular mechanisms controlling hydrogen ion homeostasis in ischemia in a somewhat more simple preparation, without the additional variable of blood flow. These mechanisms will be studied in the isolated brain slice preparation in vitro where the time course and reversibility of the effects can be determined in each slice. These studies are also designed to begin the attempt at separating the relative contribution of the different cell types (neurons, glial, endothelial cells) to observed phenomena. The fruits of these studies will be related back to the intact animal through experimental protocols designed to examine the possible influences of the hydrogen ion/volume regulation mechanisms on the active control of cerebral capillary function especially that part devoted to matching capillary recruitment to cerebral metabolic demand.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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Case Western Reserve University
Schools of Medicine
United States
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Kreisman, N R; LaManna, J C (1999) Rapid and slow swelling during hypoxia in the CA1 region of rat hippocampal slices. J Neurophysiol 82:320-9
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