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

OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) have been suggeste d to contribute to the development of increased intracranial pressure (ICP) . We recently demonstrated that human PMNs produce a novel cytochrome P450- derived arachidonic acid metabolite, 16(R)-hydroxyeicosatetraenoic acid [16 (R)-HETE], that modulates their function. It was thus of interest to examin e this novel mediator in an acute stroke model. METHODS: 16-HETE was assessed initially in a variety of human PMN and plate let in vitro assays and subsequently in an established rabbit model of thro mboembolic stroke. A total of 50 rabbits completed a randomized, blinded, f our-arm Study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot emboliza tion. The primary end point for efficacy was the suppression of increased I CP. RESULTS: In in vitro assays, 16(R)-HETE selectively inhibited human PMN adh esion and aggregation and leukotriene B-4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant sup pression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline vers us final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue pl asminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen a ctivator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg). CONCLUSION: 16(R)-HETE suppresses the development of increased ICP in a rab bit model of thromboembolic I-stroke and may serve as a novel therapeutic s trategy in ischemic and inflammatory pathophysiological states.