• DOI:10.1097/00006123-200012000-00029
• Corpus ID: 31380320

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

@article{Bednar200016RHydroxyeicosatetraenoicAA,
  title={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},
  author={Martin M. Bednar and Cordell E. Gross and Sheila R. Russell and Susan P. Fuller and Terence Patrick Ahern and Diantha B. Howard and John R. Falck and Komandla Malla Reddy and Michael Balazy},
  journal={Neurosurgery},
  year={2000},
  volume={47},
  pages={1410-1419}
}

• M. Bednar, C. Gross, +6 authors M. Balazy
• Published 1 December 2000
• Medicine, Biology
• Neurosurgery

OBJECTIVEActivated 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. METHODS16-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. RESULTSIn 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). CONCLUSION16(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.