Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits

• Published in: Experimental neurology Vol. 256; pp. 7 - 16
• Main Authors: Corser-Jensen, Chelsea E., Goodell, Dayton J., Freund, Ronald K., Serbedzija, Predrag, Murphy, Robert C., Farias, Santiago E., Dell'Acqua, Mark L., Frey, Lauren C., Serkova, Natalie, Heidenreich, Kim A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-06-2014; Elsevier
• Subjects: Adult and adolescent clinical studies; Animals; Biological and medical sciences; Blood–brain barrier; Brain - drug effects; Brain Injuries - complications; Brain Injuries - drug therapy; Brain Injuries - psychology; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - psychology; Edema; FLAP inhibitor; Hippocampus; Hippocampus - drug effects; Indoles - pharmacology; Indoles - therapeutic use; Injuries of the nervous system and the skull. Diseases due to physical agents; Leukotrienes; Leukotrienes - biosynthesis; Lipoxygenase Inhibitors - pharmacology; Lipoxygenase Inhibitors - therapeutic use; Long-term potentiation; Long-Term Potentiation - drug effects; Male; Maze Learning - drug effects; Medical sciences; Memory and learning; Neuroinflammation; Neurology; Neuropharmacology; Neuroprotective agent; Organic mental disorders. Neuropsychology; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Traumas. Diseases due to physical agents; Traumatic brain injury; Edema; 5-LO; BBB; RAWM; Traumatic brain injury; Long-term potentiation; LTP; Neuroinflammation; Blood–brain barrier; fEPSP; FLAP; RP LC–MS/MS; Leukotrienes; FLAP inhibitor; Memory and learning; TBI; EB; Gd; FPI; Hippocampus; Potentiation; Cognitive disorder; Memory; Central nervous system; Blood brain barrier; Encephalon; Learning; Acquisition process; Blood-brain barrier; Eicosanoid; Synaptic plasticity; Nervous system diseases; Pathophysiology; Arachidonic acid derivatives; Leukotriene; Flap; Head trauma
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.03.008

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.
•Leukotrienes mediate edema and blood–brain barrier permeability after TBI.•Leukotriene production contributes to lasting deficits in memory and learning.•Blocking leukotriene synthesis attenuates brain injury and cognitive impairments.•FLAP inhibitors are promising therapeutic candidates for traumatic brain injury.