title: Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits.
abstract: Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in the brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arm water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits.
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Chelsea E
authors.initials: CE
authors.lastname: Corser-Jensen
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Dayton J
authors.initials: DJ
authors.lastname: Goodell
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Freund
authors.affiliation: Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Predrag
authors.initials: P
authors.lastname: Serbedzija
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Santiago E
authors.initials: SE
authors.lastname: Farias
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
authors.affiliation: Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Frey
authors.affiliation: Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Serkova
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: kim.heidenreich@ucdenver.edu.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Heidenreich
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D002722:Chlorobenzenes
chemical_list: D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes
keywords: Blood–brain barrier; Edema; FLAP inhibitor; Hippocampus; Leukotrienes; Long-term potentiation; Memory and learning; Neuroinflammation; Traumatic brain injury