Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatmentof stroke in the rat

Objective: To examine the efficacy of an antileukocyte adhesion antibody (a nti-CD18) as an adjuvant for delayed (2 hours and 4 hours) thrombolytic the rapy (recombinant human tissue plasminogen activator [rt-PA]) in middle cer ebral artery occlusion (MCAO) in rats. Background: Thrombolytic therapy wit h rt-PA is limited in its application by a short therapeutic window. Method s: Male Wistar rats were subjected to MCAO by a single fibrin-rich clot. Th e rats were assigned to the following experimental groups: Experiment 1 (tr eatment 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; Exper iment 2 (treatment 4 hours after occlusion), 1) rt-PA alone, 2) rt-PA and a nti-CD18 antibody, and 3) nontreated control group. Neurologic deficits, in farction volume, hemorrhage, and brain myeloperoxidase (MPO) immunoreactivi ty were measured. Results: Administration of rt-PA and anti-CD18 antibody 2 hours later reduced significantly (p < 0.05) the infarct volume and improv ed neurologic deficits compared with the vehicle-treated group. Treatment w ith 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 neurol ogic deficits compared with the IgG-treated group. The combination of rt-PA and anti-CD18 antibody treatment at 4 hours reduced significantly the infa rct 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. Conclusions: The combinatio n of antileukocyte adhesion antibody and thrombolytic therapy may increase the therapeutic window for the treatment of stroke.