benzofurans and ciprostene

A pharmacological analysis was carried out to determine the possible role of aberrant calcium fluxes, vasoactive arachidonic acid metabolites, and microvascular lipid peroxidation in the development of posttraumatic spinal cord white matter ischemia. Pentobarbital-anesthetized cats were treated intravenously 30 minutes before a 500-gm-cm contusion injury to the lumbar spinal cord with one of the following test drugs: the Ca++ channel antagonists verapamil, diltiazem, or nifedipine; the cyclo-oxygenase inhibitors ibuprofen or meclofenamate; the thromboxane A2 (TXA2) synthetase inhibitor furegrelate sodium; or the stable epoprostenol (prostacyclin, or PGI2) analogue ciprostene calcium alone or in combination with furegrelate sodium. Another group of animals was pretreated for 5 days before spinal injury with a combination of the antioxidants vitamin E and selenium in high doses. The hydrogen clearance technique was used to make repeated measurements of spinal cord blood flow (SCBF) in the dorsolateral funiculus of the injured segment before and for 4 hours after injury. In 11 untreated uninjured cats, the mean preinjury SCBF was 12.7 +/- 1.5 ml/100 gm/min. Following contusion, there was a progressive decline in SCBF to 6.8 +/- 0.4 ml/100 gm/min, or 53.5% of the preinjury level at 4 hours. In comparison, the Ca++ antagonists diltiazem and nifedipine (but not verapamil) prevented a significant posttraumatic decrease in SCBF. Similarly, both cyclo-oxygenase inhibitors (ibuprofen and meclofenamate) maintained SCBF within normal limits (10 ml/100 gm/min or greater). However, neither TXA2 synthetase inhibition nor the stable PGI2 analogue alone had a significant effect in preventing ischemia, whereas a combination of the two agents did serve to support SCBF. The most impressive preservation of posttraumatic SCBF, however, was observed in the antioxidant-treated animals. Based upon these results, a hypothesis is presented concerning the pathogenesis of posttraumatic central nervous system ischemia which integrates an injury-induced rise in intracellular Ca++, the increased synthesis of vasoactive prostanoids (such as prostaglandin F2 alpha and TXA2), and progressive microvascular lipid peroxidation.

Topics: Animals; Benzofurans; Calcium Channel Blockers; Cats; Cyclooxygenase Inhibitors; Diltiazem; Dinoprost; Epoprostenol; Female; Ibuprofen; Ischemia; Male; Meclofenamic Acid; Nifedipine; Prostaglandin Antagonists; Prostaglandins F; Spinal Cord; Thromboxane A2; Verapamil; Vitamin E

The ability of the cyclooxygenase inhibitor ibuprofen to affect early neurologic recovery following a moderately severe concussive head injury was studied in male CF-1 mice. Each mouse received a 900 g-cm (50 g weight dropped 18 cm) head injury, followed within 5 minutes with a single IV dose of ibuprofen (sodium salt; 1, 3, 10, or 30 mg/kg). At 1 hour postinjury, their neurologic status was assessed using a grip test. Drug administration and neurologic evaluation were carried out blindly. A dose-related improvement in recovery was observed, with a 10 mg/kg IV dose causing a 122% increase in the mean grip test score compared to 0.9% saline treatment (p less than 0.01 by one-way ANOVA). In addition, there was a significant decrease in the number of mice in the 10 mg/kg ibuprofen group that fell off the grip test string in 0-5 seconds (i.e., that were severely impaired). In comparison, neither the selective thromboxane A2 synthetase inhibitor furegrelate sodium, the stable epoprostenol (PGI2) analog ciprostene calcium, nor the selective 5-lipoxygenase inhibitor piriprost potassium caused any therapeutic effect. The highest dose of the TXA2 synthetase inhibitor (30 mg/kg IV) actually had a statistically significant detrimental action that appeared to be due to an increase in posttraumatic cerebral hemorrhage. The possible mechanisms of the beneficial effect of ibuprofen in acute head injury are discussed in relation to an attenuation of the synthesis of vasoactive arachidonic acid metabolites (e.g., prostaglandin F2 alpha, thromboxane A2) and oxygen-free radical-induced lipid peroxidation.

Topics: Animals; Arachidonate Lipoxygenases; Benzofurans; Craniocerebral Trauma; Dose-Response Relationship, Drug; Epoprostenol; Ibuprofen; Injections, Intravenous; Lipoxygenase Inhibitors; Mice; Prostaglandin-Endoperoxide Synthases; Thromboxane-A Synthase; Time Factors