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

Martin M. Bednar, Cordell E. Gross, Sheila R. Russell, Susan P. Fuller, Thomas P. Ahern, Diantha B. Howard, J R Falck, Komandla Malla Reddy, Michael Balazy

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 languageEnglish (US)
Pages (from-to)1410-1419
Number of pages10
JournalNeurosurgery
Volume47
Issue number6
DOIs
StatePublished - 2000

Keywords

  • Cerebral ischemia
  • Hydroxyeicosatetraenoic acid
  • Intracranial pressure
  • Leukotriene B
  • Polymorphonuclear leukocyte

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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