Objective:

This study aims to elucidate the role of NETs in SAH pathophysiology and whether their inhibition can act as a therapy for clinical settings. We hypothesize that SAH-induced mice treated with the PAD4 inhibitor, GSK484, will show fewer deficits.

Background:

Neutrophil extracellular traps (NETs) are a hallmark of the immune system, activating during times of cellular stress and neovascular events. Within SAH pathophysiology, NETs can impede healing and obstruct vasculature by inducing inflammation and releasing histone/protein factors that cause vasoconstriction.

Design/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 post-SAH using composite neurobehavior exams. 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 formations were counted post-SAH in both male and female mice.

Results:

In both males and females, 70% of the SAH group treated with the PAD4 inhibitor exhibited a neuroscore comparable to the sham group and significantly higher than the SAH-only group. Similarly, the mean infarct volume for male and female mice significantly decreased when treated with the PAD4 inhibitor GSK484. Finally, the NETs count displayed an increase for the vehicle group compared to the sham group, exhibiting a negative correlation between PAD4 inhibition and NETs count.

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. Based on the results, significant recovery in behavioral outcomes is seen, along with a decrease in damaged tissue observed from the infarct volume between days. For future directions, anti-neutrophil therapeutics will be tested.