Our goal is to determine the efficacy and parameters of application of employing monoclonal antibodies against Ieukocyte adhesion molecules to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat. Our underlying hypothesis is that leukocytes, primarily neutrophils, contribute to ischemic cell damage after transient MCA occlusion. Therefore, by blocking adhesion molecule binding sites on the Ieukocyte, adhesion of the leukocyte, to the endothelium and subsequent emigration of the leukocyte into the brain parenchyma will be reduced, and concomitantly ischemic cell damage will be reduced. We will test-the effect of administration of three antibodies, anti-CDt t b, anti-CDt 8, and anti-VLA-4 on -ischemic - cell damage. Anti-CDt lb and anti-CDt 8 monoclonal antibodies will block neutrophil and monocyte adherence and emigration, while the anti-VLA-4 antibody will reduce monocytes within the ischemic lesion. A dose-response for antibody administration will be obtained as function of duration of the lVICA. Since the inflammatory response occurs well into the reperfusion period, we will also test the efficacy of administering these antibodies after onset of reperfusion, and identify the longest duration of reperfusion for which- this -intervention is effective in reducing ischemic cell damage. The mechanisms by which these leukocyte anti-adhesion molecule monoclonal antibodies reduce ischemic cell damage will be investigated. For treatment with anti-adhesion molecule antibodies and with isotype matched, controls, leukocytes (neutrophils and monocytesj will be correlated to ischemic cell damage within regions of the ischemic tissue, and neutrophil numbers will be counted using a myeloperoxidase assay. Quantitative autoradiography will be employed to measure cerebral blood flow and the permeability of the blood-brain-barrier (RlSA, AlB), with and without treatment. The proposed studies will optimize treatment of MCA occlusion and define the limits of applicability (duration of ischemia and reperfusion) of this promising therapy.
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