Delayed adjuvant therapy with the 21-aminosteroid U74006F and the anion channel blocker L644-711 does not improve outcome following thrombolytic therapy in a rabbit model of thromboembolic stroke

Abstract

Both the 21-aminosteroid U74006F, a potent inhibitor of lipid peroxidation, and L644-711, an anion channel blocker that inhibits both neutrophil and astrocyte function, have been previously shown to reduce brain injury in pretreatment paradigms of cerebral ischemia. It was therefore of interest to examine the effect of these agents in combination, when given on a delayed basis as adjuvants to thrombolytic therapy in a rabbit model of thromboembolic stroke. Animals were mechanically ventilated and arterial blood gases controlled. Core and brain temperature, intracranial pressure, and mean arterial pressure were continuously monitored. Regional cerebral blood flow and hematocrit were measured hourly. Blood samples were taken to measure neutrophil (aggregation and chemiluminescence) and platelet (aggregation) activity. Following delivery of an autologous clot via the carotid artery, all experiments were continued for an 8-hour period. U74006F (3 mg/kg I.V.) and L644,711 (12 mg/kg I.V.) or their vehicle control (n = 8, each group) were given 3.5 hours following autologous clot embolization. Both groups received tissue-type plasminogen activator (t-PA) (6.3 mg/kg I.V.), beginning 4 hours following thromboembolic stroke and continuing over a 2-hour infusion period. Infarct size was determined following staining and image analysis. In the L644,711/U74006F group, neutrophil chemiluminescence was reduced following drug therapy; however, there were no significant differences between groups regarding infarct size (50.3 +/- 8.7 vs. 49.9 +/- 10.6, treatment vs. t-PA control, mean +/- SEM), or in regional cerebral blood flow or intracranial pressure over time. It is concluded that prolonged (3.5 hours) delay of the initiation of therapy with the anion channel blocker L644,711 and the 21-aminosteroid U74006F fails to further reduce brain injury when given in combination with tissue plasminogen activator in a rabbit model of thromboembolic stroke.