363 PAD4 Inhibitor Therapy Prevents NETs and Improves SAH Outcomes

INTRODUCTION: Neutrophil extracellular traps (NETs) are a hallmark of the immune system, activating during times of cellular stress and neovascular events. Within SAH pathophysiology, NETs have the ability to impede healing and obstruct vasculature by inducing inflammation and releasing factors that cause vasoconstriction. METHODS: SAH was induced within C57 male mice via endovascular perforation. Female mice were injected with blood. Mice were then administered either GSK106 (vehicle) or GSK484 (treatment) Mice were assessed behaviorally daily through composite neurobehavior exams. Microthrombi count was assessed at -2 from Bregma in the whole slice. In–vivo MRI was used to evaluate cerebral blood flow and infarct volume 1 day and 5 days post SAH. Behavior was analyzed using a parametric two-way ANOVA test and MRI data were analyzed using a two-way ANOVA with post hoc testing. NET formation was counted post-SAH in both male and female mice. RESULTS: In both males and females, SAH groups exhibited an increase in neuroscore that was near that of the sham group, showing recovery of negative outcomes following SAH. Similarly, the mean infarct volume for male and female mice exhibited a decrease when treated with the PAD4 inhibitor. Overall, the NET count displayed a large increase for the vehicle group and showed a level similar to the sham group when looking at mice treated with the inhibitor. CONCLUSIONS: The PAD4 inhibitor, GSK484, has been shown to improve recovery in SAH-aged mice and may be a viable therapy for positive outcomes in SAH animals.