Ischemic brain injury evokes an endogenous brain parenchymal cell damage as well as an exogenous inflammatory response, which includes infiltration and accumulation of polymorphonuclear leukocytes and monocytes/macrophages, and microvascular proliferation. The migration and accumulation of neutrophils into the ischemic tissue after reperfusion is not only associated with tissue repair processes, but also may result in injury to potentially viable tissue. We propose to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking the intercellular adhesion molecule 1 (ICAM-1), a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion.
Three specific aims and hypotheses will be tested.
Aim 1 : The effect of administration of a monoclonal antibody to the rat ICAM-1 on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) and permanent MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with the ICAM-1 glycoprotein reduces ischemic cell damage after transient MCA occlusion.
Aim 2 : We will measure the temporal profiles of expression of ICAM-1 and ICAM-1 mRNA in brain after transient MCA occlusion. Hypothesis: MCA occlusion results in an increase of both ICAM-1 message and protein in ischemic brain.
Aim 3 : Mechanisms by which the anti-ICAM-1 reactive antibody reduces ischemic cell damage will be investigated. 3(a): We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis: Anti-ICAM-1 antibody causes a reduction of neutrophils in the ischemic tissue. Infiltration of neutrophils into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 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 (CBF) and extending the duration of ischemia. Our long term objective is to develop a therapeutic intervention (anti- ICAM-1 antibody) to be employed after the onset of ischemic stroke.
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