((5-6-dichloro-2-3-9-9a-tetrahydro-3-oxo-9a-propyl-1h-fluoren-7-yl)oxy)acetic-acid and Cerebrovascular-Disorders

Topics: Amino Acids; Animals; Astrocytes; Biological Transport; Cats; Cell Size; Cells, Cultured; Central Nervous System Diseases; Cerebrovascular Disorders; Craniocerebral Trauma; Disease Models, Animal; Diuretics; Encephalomyelitis, Autoimmune, Experimental; Fatty Acids; Fluorenes; Free Radicals; Humans; Hydrogen-Ion Concentration; Hypotonic Solutions; Membrane Potentials; Potassium; Rats; Rats, Sprague-Dawley

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.

Topics: Animals; Anions; Biological Transport; Cerebrovascular Circulation; Cerebrovascular Disorders; Chemotherapy, Adjuvant; Disease Models, Animal; Female; Fluorenes; Male; Neuroprotective Agents; Pregnatrienes; Rabbits; Thromboembolism; Thrombolytic Therapy; Time Factors; Treatment Outcome

We studied the anion transport inhibitor L-644,711, which is known to reduce astrocyte swelling and excitotoxin release in primary astrocyte culture, in two models of thromboembolic stroke to assess its capacity to influence ischemic brain injury.. New Zealand White rabbits were used in this study. The two models include autologous clot embolized to the brain via the carotid artery, with one model using a transient period of systemic hypotension. Cerebral blood flow was determined by the hydrogen clearance method, intracranial pressure was measured with a fiberoptic transducer, and infarct size was assessed with triphenyltetrazolium chloride staining of the coronally sectioned brain. Both models received a 2-hour infusion of L-644,711 (total dose, 12 mg/kg) beginning 20 minutes before embolization.. In both the normotensive (p less than 0.01) and the hypotensive (p less than 0.05) model, treatment with L-644,711 resulted in a significant reduction in infarct size and a significant improvement in regional cerebral blood flow (p less than 0.03, normotensive model, and p less than 0.05, hypotensive model). Raised intracranial pressure, unique to the hypotensive model, was abolished by the administration of L-644,711 (p less than 0.05). A hyperglycemic response associated with embolization, also unique to the hypotensive model, was significantly reduced by the administration of L-644,711 (p less than 0.05).. The ability of L-644,711 to limit brain injury in two related models of thromboembolic stroke suggests a potential therapeutic role for anion channel blockers in cerebral ischemia.

Topics: Animals; Astrocytes; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Female; Fluorenes; Intracranial Embolism and Thrombosis; Intracranial Pressure; Male; Rabbits