Early and Sustained Increases in Leukotriene B(4) Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients

Leukotriene B(4) (LTB(4)) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB(4) levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB(4) levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB(4) rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB(4) levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A(4) hydrolase (LTA(4)H), highlighting the pivotal contributions of neutrophils as a source of LTB(4). Importantly, rise in plasma LTB(4) levels corresponded with an increase in LTB(4) amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB(4) levels. Pre-stroke LTB(4) loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB(4) pathway might be a viable treatment strategy for acute ischemic stroke. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00787-4) contains supplementary material, which is available to authorized users.