Investigation on a novel therapeutic agent against ischemic brain edema.

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The aim of this project was to investigate on the therapeutic effect of free radical scavengers on ischemic brain edema and on the mechanism of action of these drugs. Pertinent findings are as described below:1) The activity of arachidonate cascade is generally enhanced within the ischemic brain; 2) The increase of lipoxygenase products (HETEs) in the ischemic brain was for the first time demonstrated; 3) The eicosanoid synthetic capacity of brain microvessels paralleled the time course of brain edema; 4) The cyclooxygenase as well as lipoxygenase activities within brain microvessels were significantly stimulated by a lipid hydroperoxide of arachidonic acid, 15-HPAA; 5) The activity of Na,K-ATPase of brain microvessels was also stimulated by 15-HPAA and the activation of lipoxygenase pathway was involved in this stimulation; 6) A specific inhibitor of Na,K-ATPase, i.e., ouabain significantly suppressed edema formation when perfused into the distal branch of occluded middle cerebral artery. Since the influx of water across the blood-brain barrier is attributed to the influx of sodium, the enhanced activity of Na,K-ATPase within brain microvessels may be involved in the pathogenetic mechanism underlying ischemic brain edema. 7) Free radical scavengers such as vitamin E and AVS significantly suppresed the 15-HPAA-induced stimulation of Na,K-ATPase in vitro and ameliorated brain edema in vivo. Taken together, these pieces of evidence suggest that the enhanced activity of lipoxygenase pathway and subsequent stimulation of Na,K-ATPase within brain microvessels play a significant role in edema formation. The increased level of ambient free radicals may precede the above sequence of events and this may explain the observed anti-edema effect of free radical scavenger, AVS.