Abstract
OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) have been suggested 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 examine this novel mediator in an acute stroke model. METHODS: 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP. RESULTS: In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 ± 1.2 to 13.1 ± 2.7 mm Hg, baseline versus 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 plasminogen 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 activator 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 rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.
Original language | English (US) |
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Pages (from-to) | 1410-1419 |
Number of pages | 10 |
Journal | Neurosurgery |
Volume | 47 |
Issue number | 6 |
DOIs | |
State | Published - 2000 |
Keywords
- Cerebral ischemia
- Hydroxyeicosatetraenoic acid
- Intracranial pressure
- Leukotriene B
- Polymorphonuclear leukocyte
ASJC Scopus subject areas
- Surgery
- Clinical Neurology