15-hydroperoxy-5-8-11-13-eicosatetraenoic-acid and Brain-Ischemia

A survey on literature reports and our own experimental studies on the pathogenetic mechanisms underlying ischaemic brain oedema is given and a new concept proposed. In regional incomplete ischaemia the lipoxygenase activity is enhanced, presumably caused by an increase of free radicals and hydroperoxides, leading to an enhancement of endothelial Na+, K+-AtPase and increased sodium and water transport from blood to brain. The aggravation of brain oedema and post-ischaemic hypoperfusion following recirculation appears to be mainly due to an activation of the cyclo-oxygenase pathway with release of oxidants from PGG2, which causes non-specific but detrimental damage to the endothelial and parenchymal cells. This new concept may open future perspectives in treatment which are briefly discussed.

Topics: Animals; Arachidonic Acids; Biomechanical Phenomena; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Capillaries; Cerebrovascular Circulation; Eicosanoic Acids; Free Radicals; Humans; Leukotrienes; Lipid Peroxides; Lipoxygenase; Oxygen; Prostaglandin-Endoperoxide Synthases; Sodium-Potassium-Exchanging ATPase; Time Factors

To know the mechanism underlying ischemic brain edema, a time-course analysis of the eicosanoid synthetic capacity of brain microvessels was carried out using unilateral, middle cerebral artery (MCA)-occluded rats. Concomitant with the development of brain edema the synthetic capacity of all products, including cyclooxygenase and lipoxygenase products, increased significantly. Next the effects of 15-hydroperoxyarachidonic acid (15-HPAA) on the synthetic capacity of microvessels were examined. The drug caused a generalized increase of each product, the profile of which was similar to that obtained with ischemic hemispheres, although the ratios of each product differed somewhat among them. The enhanced synthesis of eicosanoids by 15-HPAA was markedly suppressed by radical scavengers such as alpha-tocopherol, hydroquinone, and 1,2-bis(nicotineamide)-propane. Furthermore, the evolution of brain edema was virtually suppressed by the systemic administration of 1,2-bis(nicotineamide)-propane. The above result suggests that the enzyme activity of the arachidonic acid (AA) cascade of microvessels is stimulated by its own products. Such a mechanism will form a vicious cycle that accelerates the accumulation of free radicals within microvessels and thus may play a role in the progressing disruption of the blood-brain barrier (BBB) following ischemia.

Topics: Animals; Arachidonic Acids; Body Water; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Eicosanoic Acids; Free Radicals; Leukotrienes; Lipid Peroxides; Male; Microcirculation; Potassium; Rats; Rats, Inbred Strains; Sodium; Time Factors