16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocytes and reduces intracranial pressure in a rabbit model of thromboembolic stroke

摘要: OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic [16(R)-HETE], modulates their function. It was thus interest examine this mediator in an acute stroke model. METHODS: 16-HETE assessed initially variety PMN and platelet vitro assays subsequently established rabbit model thromboembolic stroke. A total 50 rabbits completed randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were 7 hours after autologous clot embolization. The primary end point for efficacy suppression ICP. RESULTS: In assays, 16(R)-HETE selectively inhibited adhesion aggregation leukotriene B4 synthesis. model, animals received significant ICP (7.7 +/- 1.2 13.1 2.7 mm Hg, baseline versus final 7-h time point, mean standard error), compared with either vehicle-treated group 0.9 15.8 2.6 Hg) activator-treated (7.6 0.6 13.7 2.1 Hg). combination plus activator no change duration protocol (8.6 11.1 CONCLUSION: suppresses may serve as therapeutic strategy ischemic inflammatory pathophysiological states.