Antagonism of neutrophil adherence in the deteriorating stroke model in rabbits

Abstract

✓ Adhesion of leukocytes to the endothelium can occur in a few hours after the onset of ischemia, and the actions of leukocytes have been suggested to aggravate reperfusion injury. Adhesion is a prerequisite for the harmful leukocyte actions. Rapid mediation of leukocyte adhesion and aggravation of reperfusion injury can occur through production of platelet-activating factor (PAF). The authors hypothesized that prevention of leukocyte adhesion during ischemia reperfusion would have beneficial effects and that these effects might be enhanced by a PAF antagonist. To test this hypothesis, rabbits were anesthetized with pentobarbital and subjected to severe spinal cord ischemia (25 minutes) followed by 30 minutes of reperfusion, at which time either vehicle, antibody against the CD11/CD18 (anti-CD) leukocyte adhesion molecule (1 mg/kg), or the anti-CD and PAF antagonist, WEB 2086 (3 mg/kg), was administered intravenously and the animals were monitored for 6.5 hours. Using a score from 0 to 5, recovery of motor function was improved at 5.5 hours by the CD antibody (2.0 ± 0.5 versus 0.4 ± 0.2 in the six animals in the vehicle group, p < 0.05). No further improvement was induced by WEB 2086 in the six anti-CD treated animals (1.6 ± 0.7). Spinal cord blood flow (laser Doppler flowmetry) at 6 hours was at the preischemic level in the control animals (−7% ± 20%), but clearly increased in the anti-CD group (+73% ± 29%, p < 0.5). The severity of blood-brain barrier damage in the spinal cord gray matter was decreased by the treatments. Extravasation of intravenously injected Evans blue albumin (EBA), measured by detection of EBA fluorescence, was reduced by approximately 50% in both treated groups (p < 0.05). The number of morphologically normal motor neurons in the lumbar anterior horns of the infarcted spinal cord showed protection in the seven animals in the anti-CD treated group at 6.5 hours: 12.7 ± 1.7 versus 5.3 ±1.6 (vehicle), p < 0.05 without an additional effect by PAF antagonist 12.2 ± 2.6 (anti-CD + WEB 2086). Our results suggest that ultraacute treatment of reperfusion injury based on special inhibition of leukocyte effects may be beneficial. Platelet-activating factor antagonism failed to enhance this therapeutic effect, which may suggest dependency on a common mechanism.