Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat.

Abstract

To examine the efficacy of an antileukocyte adhesion antibody (anti-CD18) as an adjuvant for delayed (2 hours and 4 hours) thrombolytic therapy (recombinant human tissue plasminogen activator [rt-PA]) in middle cerebral artery occlusion (MCAO) in rats. Thrombolytic therapy with rt-PA is limited in its application by a short therapeutic window. Male Wistar rats were subjected to MCAO by a single fibrin-rich clot. The rats were assigned to the following experimental groups: Experiment 1 (treatment 2 hours after embolization), 1) rt-PA, 2) anti-CD18 antibody, 3) rt-PA and anti-CD18 antibody, 4) immunoglobulin (Ig) G, and 5) vehicle; Experiment 2 (treatment 4 hours after occlusion), 1) rt-PA alone, 2) rt-PA and anti-CD18 antibody, and 3) nontreated control group. Neurologic deficits, infarction volume, hemorrhage, and brain myeloperoxidase (MPO) immunoreactivity were measured. Administration of rt-PA and anti-CD18 antibody 2 hours later reduced significantly (p < 0.05) the infarct volume and improved neurologic deficits compared with the vehicle-treated group. Treatment with rt-PA alone improved neurologic deficits significantly and reduced mean infarct volume compared with the vehicle-treated group. However, treatment with anti-CD18 antibody neither reduced infarct volume nor improved neurologic deficits compared with the IgG-treated group. The combination of rt-PA and anti-CD18 antibody treatment at 4 hours reduced significantly the infarct volume and MPO immunoreactive cells compared with rt-PA treatment alone at 4 hours, and reduced neurologic deficits compared with rt-PA treatment alone and compared with the nontreated animals. The combination of antileukocyte adhesion antibody and thrombolytic therapy may increase the therapeutic window for the treatment of stroke.