Effect of MCI-186 on brain edema in rats.

Abstract

We induced brain edema in 72 rats by injecting 5 fil of 3.0% wt vol polyvinyl acetate into the left internal carotid artery, producing permanent embolization in the left cerebral hemisphere, which developed ipsilateral brain edema reproducibly. Edema was assessed 24 hours after embolization by determining the brain water content and the sodium and potassium concentrations. In this model, the free radical scavenger MCI-186 at 1.0 and 3.0 mg/kg i.v. prevented brain edema in a dose-dependent manner. At 3.0 mg/kg i.v., MCI-186 significantly reduced water content by 1.5% and improved the sodium-potassium balance to within the normal range in the embolized left hemisphere. Dexamethasone at 1.0 mg/kg i.v. did but at 3.0 mg/kg i.v. did not significantly inhibit the development of brain edema. Indomethacin at 4.0 mg/kg i.p. had no effect on brain edema. We suggest that the cyclooxygenase metabolites of arachidonic acid liberated from neuronal cell membrane phospholipids are not likely to be involved in the pathogenesis of permanent brain edema induced by polyvinyl acetate. Our results suggest that MCI-186 attenuates brain edema by suppressing the production of lipoxygenase metabolites, including free radicals or lipid peroxides, and that it may prove valuable for the treatment of brain edema associated with cerebral ischemia. (Stroke 1989;20:1236-1240) A lthough brain edema is a serious clinical complication in acute cerebrovascular disorders, there are few drugs available for therapeutic intervention. For this reason, many attempts have been made to develop new agents for the therapy of brain edema. However, experimental brain edema induced by permanent and transient ischemia responds differently to drugs. For example, indomethacin effectively reduces the formation of edema in animals subjected to transient ischemia but has no such action in prolonged cerebral ischemia.1 Thus, the choice of an appropriate experimental model is crucial in the evaluation of new drugs to counteract brain edema. A major remaining difficulty is that the biochemical mechanisms underlying brain edema formation are poorly understood. Among the existing hypotheses are that changes in membrane phospholipids and in arachidonic acid metabolites play an important role in the pathogenesis of brain edema. Received November 17, 1988; accepted April 10, 1989. genase activity 6 in vitro. In consideration of these factors the antiedema activity of MCI-186 has been evaluated compared with indomethacin and dexamethasone in a model of permanent brain infarction induced by polyvinyl acetate (PVA) 7 in rats. We sought to substantiate the hypothesis that the cyclooxygenase metabolites of arachidonic acid are unlikely to be involved in the development of brain edema. Materials and MethodsWe used 72 male Wistar rats weighing 280-310 g housed four to a cage 17.5x30.0x34.5 cm equipped with wood shavings for bedding. Food and water were provided ad libitum. The temperature in the animal rooms was maintained at 23 ±1° C, and the light:dark schedule was 12^12 hours...

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