Abstract WP214: Inhibition Of 12/15-Lipoxygenase Attenuates Delayed Vasospasm After Subarachnoid Hemorrhage In Mice

Approximately 30% of subarachnoid hemorrhage (SAH) patients who survive the initial ictus develop delayed cerebral ischemia (DCI) 4 to 10 days following SAH. Multiple clinical studies indicate the cause of DCI is multifactorial and includes vasospasm. 12/15-Lipoxygenase (LOX), enzymes that metabolize arachidonic acid into bioactive lipid metabolites, such as 12-HETE and 15-HETE, are expressed in several cell types of the brain including neurons, and microglia. Previous work has shown that 12/15-LOX has detrimental effects on brain vasculature and neurons, triggers inflammation, and thrombosis. In a previous study, inhibition of 12/15-LOX was beneficial in reducing early brain injury in mice after SAH. We hypothesize that inhibition of 12/15-LOX would attenuate delay vasospasm and reduce DCI in SAH mice. C57BL/6 mice of both sexes were randomized into Sham+Vehicle, SAH+Vehicle, SAH+ML351. Vehicle and ML351 (LOX inhibitor, 25mg/kg) were intravenously injected 15 minutes after SAH. 12/15-LOX -/- mice of both sexes were randomized into sham or SAH. Behavior was assessed daily until euthanasia on day 5 for analysis of vasospasm. Following SAH, there, there was an increased expression of 12/15-LOX in brain endothelial cells. Inhibition of 12/15-LOX in C57BL/6 males reduced large artery vasospasm and microvessel constriction, improved functional outcome, and lowered DCI incidence. In female C57BL/6 mice, inhibition of 12/15-LOX also reduced vasospasm and microvessel constriction, and ameliorated behavioral deficits. 12/15-LOX -/- displayed better behavior and have less delayed vasospasm. The findings of this study suggest that inhibition of 12/15-LOX is therapeutically beneficial for male and female mice after SAH via preventing delay vasospasm and DCI.