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.