Investigation on a novel therapeutic agent against ischemic brain edema.

本课题旨在探讨自由基清除剂对缺血性脑水肿的治疗作用及其作用机制。结果表明：（1）缺血脑内花生四烯酸级联反应活性普遍增强，（2）首次发现脑内脂氧合酶产物（HETE）增加，（3）脑微血管合成类花生酸的能力与脑水肿的时间进程有关，（4）脑内脂质代谢产物（HETE）增加。4）花生四烯酸脂质过氧化氢能显著刺激脑微血管内环氧合酶和脂氧合酶的活性，15-HPAA; 5）15-HPAA还能刺激脑微血管Na，K-ATP酶活性，并参与激活脂氧合酶途径;哇巴因在灌注到闭塞的大脑中动脉的远端分支时显著抑制水肿形成。由于血脑屏障的水内流是由钠内流引起的，因此脑微血管内Na，K-ATP酶活性的增强可能参与了缺血性脑水肿的发病机制。7)自由基清除剂如维生素E和AVS在体外可显著抑制15-HPAA对Na，K-ATP酶的刺激作用，在体内可明显减轻脑水肿。总之，这些证据表明，脑微血管内脂氧合酶途径活性的增强和随后的Na，K-ATP酶的刺激在水肿形成中起重要作用。环境自由基水平的增加可能先于上述事件序列，这可以解释观察到的自由基清除剂AVS的抗水肿作用。

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.