title: 16(R)-hydroxyeicosatetraenoic acid, a novel cytochrome P450 product of arachidonic acid, suppresses activation of human polymorphonuclear leukocyte and reduces intracranial pressure in a rabbit model of thromboembolic stroke.
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, 1 6(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).
  
  
  CONCLUSIONS
  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.
authors: Division of Neurosurgery, University of Vermont, Burlington 05405-0068, USA. mbednar@cyberzone.net
authors: M M
authors: MM
authors: Bednar
authors: C E
authors: CE
authors: Gross
authors: S R
authors: SR
authors: Russell
authors: S P
authors: SP
authors: Fuller
authors: T P
authors: TP
authors: Ahern
authors: D B
authors: DB
authors: Howard
authors: J R
authors: JR
authors: Falck
authors: K M
authors: KM
authors: Reddy
authors: M
authors: M
authors: Balazy
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D002542:Intracranial Embolism and Thrombosis / Q000150:complications*; D007427:Intracranial Pressure / Q000187:drug effects*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D016037:Single-Blind Method; D020521:Stroke / Q000209:etiology* / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: C410424:16-hydroxy-5,8,11,14-eicosatetraenoic acid; D005343:Fibrinolytic Agents; D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D010959:Tissue Plasminogen Activator