Abstract 3630: Function-Blocking Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Antibody Injection is Neuroprotective after Focal Cerebral Ischemia

Abstract

Introduction: Extracellular metalloproteinase inducer, EMMPRIN, is a cell surface glycoprotein found on endothelial cells and astrocytes and has a key role in the expression of MMPs. It was reported that EMMPRIN expression is upregulated in a mouse model of permanent cerebral ischemia and that EMMPRIN co-localized with MMP-9 in infarcted tissue. There is evidence to support that elevation of MMP activity contributes to injury after stroke and that inhibition of MMPs can reduce infarct volume in rats. In this study we hypothesized that inhibition of EMMPRIN with a function-blocking antibody would reduce infarct volume and improve stroke outcome in mice subjected to a MCAO stroke through reduction in MMP activation. Methods: Transient 90-minute middle cerebral artery occlusion (MCAO) was performed on male wild-type mice treated with vehicle, rat IgG2a (eBioscience), or with function blocking anti-EMMPRIN antibody (eBioscience) injected via tail vein. A single injection was given at stroke onset. Mice were sacrificed at 48 hours post reperfusion. Brains were harvested for TTC staining (n=4/group; significance p<0.05). A second cohort of vehicle and drug treated mice (n=3 vehicle, n=7 drug) were subjected to transient 90-minute middle cerebral artery occlusion and were sacrificed at 72 hours. These mice were given the initial dose at stroke onset and an additional dose at 48 hours. Both cohorts were subjected to behavioral analysis using a modified 4 point scoring system. Results: Mice treated with the function blocking EMMPRIN antibody had smaller infarct volumes when compared with vehicle treated animals. This reduction in damaged tissue was consistent in the cortex, striatum and total hemisphere of each group. Drug treated mice had improved behavior scores when compared to vehicle treated mice at both the 48hr and 72hrs time points. Furthermore, vehicle treated mice had higher mortality rates (20% at 48hrs and 66% at 72hrs) than drug mice (0% at 48hrs and 14% at 72hrs) at both time points. Discussion: Animals treated with a function-blocking antibody to EMMPRIN presented with less infarct volume and better behavior scores than similar animals treated with vehicle. Thus, EMMPRIN inhibition is neuroprotective. Considering monoclonal antibody therapy has been successful in the treatment of other diseases, this data suggests that inhibition of EMMPRIN via administration of an antibody could have therapeutic potential for stroke patients.