rLOAD: does sex mediate the effect of acute antiplatelet loading on stroke outcome

BACKGROUND: Biologic sex can influence response to pharmacologic therapy. The purpose of this proof-of-concept study was to evaluate the medicating effects of estrogen in the efficacy of acute antiplatelet loading therapy on stroke outcome in the rabbit small clot embolic model. METHODS: Female and male (20/group) New Zealand White rabbits were embolized to produce embolic stroke by injecting small blood clots into the middle cerebral artery via an internal carotid artery catheter. Two hours after embolization, rabbits were treated with standard dose antiplatelet loading (aspirin 10 mg/kg plus clopidogrel 10 mg/kg). Primary outcome measures were platelet inhibition, behavioral outcome P(50) (the weight of microclots (mg) that produces neurologic dysfunction in 50% of a group of animals), and effect of endogenous estrogen on outcome. RESULTS: For the first time in a non-rodent model of stroke, it was found that higher endogenous estrogen levels resulted in significantly better behavioral outcome in female subjects (r(s) −0.70, p < 0.011). Platelet inhibition in response to collagen, arachidonic acid, and adenosine diphosphate (ADP) was not significantly different in females with higher vs. lower estrogen levels. CONCLUSIONS: Behavioral outcomes are improved with females with higher endogenous estrogen levels treated with standard dose antiplatelet loading. This is the first non-rodent study to demonstrate that higher endogenous estrogen levels in female rabbits appear to be neuroprotective in ischemic stroke. This research supports the further study of the effect of endogenous estrogen levels on outcome with standard dose antiplatelet loading in stroke patients not eligible for revascularization therapies.