Brain eicosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema.

Abstract

The relation of brain eicosanoids to progression of cerebral edema was studied in stroke-resistant spontaneously hypertensive rats subjected to incomplete global brain ischemia induced by bilateral occlusion of the common carotid arteries. Thromboxane B 2 and 6-keto prostaglandin F lo levels were significantly elevated 5 minutes after reperfusion but returned to control levels by 30 minutes. In contrast, leukotriene C 4 levels increased 2 hours after bilateral common carotid artery occlusion and peaked 30 minutes after reperfusion, with higher levels persisting until 60 minutes after reperfusion. Cerebral ischemia was accompanied by cerebral edema early after reperfusion. The edema correlated with increased leukotriene C 4 levels. That the increased brain water content was causally related to an increase in leukotriene C 4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861. Both inhibitors suppressed the increased leukotriene C 4 and brain water contents after reperfusion. Our results indicate that leukotriene C 4 is closely associated with an induction of ischemic cerebral edema. (Stroke 1988;19:372-377) F atty acids are liberated from the plasma membranes of ischemic tissue through various pathways. 1 " 3 It is believed that these free fatty acids, particularly arachidonic acid, aggravate cell damage imposed on ischemic brain. Arachidonic acid has been the focus of repeated investigation as it relates to brain edema* 4 " 8 and endothelial cell damage of cerebral arteries. 9When the brain is subjected to severe ischemia, the amount of free arachidonic acid increases abruptly and then decreases gradually when circulation is restored. Since increased levels of arachidonic acid persist when the oxygen supply is restored, conditions exist for enhanced oxidation of arachidonic acid. For example, recirculation is accompanied by a prominent increase in prostaglandins, 10 " 12 which are formed from arachidonic acid by cyclooxygenase. Among these prostaglandins, thromboxane A 2 (TXA 2 ), which is derived primarily from platelets, has potent platelet aggregating and vasoconstrictor effects. By contrast, prostaglandin I 2 (PGI 2 ), which is derived predominantly from vascular endothelial cells, acts to prevent platelet aggregation and vasoconstriction. TXA 2 and PGI 2 are rapidly converted to the stable metabolites TXB 2 and 6-keto-PGF,,,. Received August 30, 1986; accepted September 3, 1987. 5-lipoxygenase dehydrase to leukotrienes. Of these substances, leukotriene C 4 (LTC 4 ) has particularly strong vasoconstrictor activity and promotes increased vascular permeability, perhaps by damage to the blood-brain barrier. 1516We examined the effect of incomplete global cerebral ischemia on the levels of TXB 2 , 6-keto-PGF, a , and LTC 4 in the brain of stroke-resistant spontaneously hypertensive rats (SHRSR) and the relation between LTC 4 and the progression of cerebral edema. (2-Amino -4 -1 -butyl -6-(ct-hydroxy-4-chlorobenzy l)phenolhydrochloride (ONO-LP-01...

Synthesis of Lipoxin A4by 5-Lipoxygenase Mediates PPARγ-Dependent, Neuroprotective Effects of Rosiglitazone in Experimental Stroke

“…First, this compound, depending on the dose, decreased or did not affect infarct volume on its own, suggesting a weak deleterious role of 5-LO in brain ischemia, in agreement with previous reports (Minamisawa et al, 1988;Mabe et al, 1990;Baskaya et al, 1996;Ciceri et al, 2001;Kitagawa et al, 2004;Jatana et al, 2006). Second, after administration of rosiglitazone, BWA4C inhibited the neuroprotective effect of this glitazone on infarct outcome.…”

The role of bradykinin in mediating ischemic brain edema in rats.

“…It was recently reported that prostaglandin synthesis and leukotriene synthesis were related to the occurrence of ischemic cerebral edema. [19][20][21][22] It is notable that the kallikrein-kinin system has been closely associated with the prostaglandins and leukotrienes.…”

Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia.

“…They include nonpeptidoleukotrienes that are chemotactic, 36 peptidoleukotrienes that increase vascular permeability 67 and provide potent vasoconstriction, 68 Figure 2). ND, not determined.…”