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.