EVALUATION OF ANTI-ADHESION MOLECULE THERAPY AFTER MCA OCCLUSION IN THE RAT

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Our goals are; to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking leukocyte adhesion molecule receptors (CD11b, LFA-1), to investigate mechanisms by which blocking these receptors reduce ischemic cell damage, and to bring to fruition magnetic resonance imaging as a non-invasive method of assessing the response of ischemic tissue to a therapeutic intervention. To accomplish these goals we will employ experiments associated with three Specific Aims. Aim 1: The effect of anti-(CD11b, LFA-1) monoclonal antibodies on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage after transient MCA occlusion. Aim 2: Mechanisms by which the anti-CD11b and anti-LFA-1 reactive antibodies reduce ischemic cell damage will be investigated. 2(a); We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis; Infiltration of leukocytes, primarily neutrophils, into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 2 (b). We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis; Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow. 2(c): The permeability of the blood-brain barrier (BBB) will be evaluated at various times after transient MCA occlusion. Hypothesis; Neutrophils may contribute in part to ischemic cell damage by interacting with the capillary endothelium and thereby increasing the permeability of the BBB to water and neurotoxic substances. Aim 3: We will employ NMR methodology (Perfusion Imaging, Diffusion Weighted Imaging (DWI), T1 & T2 Imaging) to assess the physiological changes and efficacy of the anti- integrin therapeutic intervention. Hypothesis: With effective leukocyte anti-adhesion molecule therapy, the temporal profiles and values of the apparent diffusion constant of water (ADC)w) and CBF in the ischemic tissue will be modified, and the volume of the lesion as measured by T2 weighted imaging will be reduced compared to animals without antibody.