Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger.

Abstract

Regional changes in the amount of free fatty acids, polyphosphoinositides, and water content in the cerebral cortex were examined using a middle cerebral artery occlusion model of rats. The amount of various free fatty acids increased as polyphosphoinositides decreased during 3 and 6 hours of ischemia in the occluded middle cerebral artery territory. After 3 hours of reperfusion following 3 hours of ischemia, free fatty acids partially recovered while polyphosphoinositides did not. Water content increased significantly after 3 and 6 hours of ischemia, and a further increase was found after 3 hours of reperfusion following 3 hours of ischemia. The change of polyenoic fatty acids in this occluded middle cerebral artery territory was much smaller than that in the case of decapitation ischemia, although the amounts of polyphosphoinositides and monoenoic and saturated fatty acids showed almost identical changes in both cases, probably because polyenoic fatty acids may be washed out and/or peroxidatively consumed in the middle cerebral artery occlusion model due to its residual blood flow. Changes in the area surrounding the occluded middle cerebral artery territory were similar to the above results, although less dramatic However, there was no change in free fatty acids, polyphosphoinositides, and water content in the contralateral cortex. A novel free radical scavenger (MCI-186), which prevents both nonenzymatic peroxidation and lipoxygenase activity in vitro, markedly attenuated the ischemic and postischemk brain swelling. These results suggest that free radical mechanisms may be involved in ischemk and postischemic brain edema. A peroxidative mechanism has been implicated as one of the detrimental factors in ischemic and postischemic brain cell damage. 1 "4 Since Demopoulos 5 indicated the possibility of free radical damage in ischemic brain, various approaches have been tried in an effort to detect some species of oxygen radicals in the ischemic or postischemic brain. However, all attempts have failed to detect oxygen radicals in vivo and in situ because of their short half-lives and/or because of methodologic difficulties involved in trapping and extracting such radicals.*"" Due to the above reasons, only indirect evidence has been obtained indicating the generation of free radicals during and after ischemia. Such evidence includes decreases in ascorbate (reduced form) and ot-tocopherol and an increase in conjugated dienes. 112 -13 Thus, although no radical species have yet been directly detected, it seems to be widely accepted that a certain species of free radicals may exist and may play a role in ischemic and/or postischemic brain damage. 1 ' 5 There are two pathways generating peroxidative reactions in damaged brain as well as in any tissue. One is an auto-oxidation (nonenzymatic peroxidation) and the other is enzyme-processing peroxidation. Nonenzymatic peroxidations have been artificially generated in vitro using brain slices, and they were shown to induce brain swelling. 14 " 17 Cell damage induced by t...

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