Arachidonic acid metabolite production following focal cerebral ischemia: Time course and effect of meclofenamate

Abstract

Arachidonic acid metabolites have been implicated in the development of cerebral edema following ischemia. To define the time course of metabolite production, subtemporal craniectomies were performed on 60 male Sprague-Dawley rats (350–400 g). Thirty rats underwent middle cerebral artery occlusion while 30 rats underwent craniectomy alone. Five rats in each of two groups (middle cerebral artery occlusion and sham) were sacrificed at 15 minutes, 1 hour, 4 hours, 1 day, 3 days, and 6 days. The cerebral hemispheres were removed and divided in the midsagittal plane. Each hemisphere was immediately frozen in isopentane cooled in dry ice and stored at −70°C. Tissue prostaglandins E 2 and 6-keto F 1, and leukotrienes (LT) B 4 and C 4 were measured by radioimmunoassay. Prostaglandin E 2 and 6-keto prostaglandin F 1α, were significantly elevated at 15 minutes in the middle cerebral artery occlusion hemispheres (p < 0.05). Prostaglandins were not significantly elevated after 15 minutes. LT B 4 and C 4 were never significantly elevated. Meclofenamate, a nonsteroidal anti-inflammatory agent, was administered to 21 additional rats. Seven controls underwent middle cerebral artery occlusion alone, 7 were given intraperitoneal meclofenamate (20 mg/kg) 30 minutes prior to middle cerebral artery occlusion, and 7 underwent middle cerebral artery occlusion followed immediately by intraperitoneal meclofenamate (20 mg/kg). The animals were sacrificed at 15 minutes and similarly studied. There was a significant reduction of prostaglandin E 2 and 6-keto prostaglandin F 1α following pretreatment with meclofenamate ( p < 0.01 and p < 0.05). In pretreated rats, leukotrienes were not affected by meclofenamate. Similarly, prostaglandins and leukotrienes did not change when meclofenamate was administered after middle cerebral artery occlusion. We conclude that cyclo-oxygenase metabolite production begins within 15 minutes of middle cerebral artery occlusion. Treatment with meclofenamate prior to middle cerebral artery occlusion significantly reduced cyclo-oxygenase metabolite production, suggesting a protective effect of meclofenamate against ischemia-induced elevations of vasoactive prostaglandins implicated in the development of cerebral edema. Lip-oxygenase metabolite production was not affected by middle cerebral artery occlusion or pharmacological intervention.