ACTIVATING PROGESTERONE RECEPTOR IMPROVES VASCULAR PERFUSION AND REDUCES NEUTROPHIL AGGREGATION AFTER ISCHEMIC STROKE RECANALIZATION IN FEMALE AND AGED MICE

Ischemic stroke remains a leading cause of death and disability, with older women experiencing disproportionately worse clinical outcomes. Although the current treatment, namely recanalization, reopens the occluded vessel, microvascular dysfunction driven in part by neutrophil aggregation limits effective tissue reperfusion. Given the immunomodulatory properties of progesterone, we investigated the therapeutic potential of NTS-104, a progesterone receptor agonist, to regulate post-recanalization neutrophil activity and microvascular reperfusion.
Using a murine model of ischemic stroke with recanalization, we examined acute (3-hour recovery; N=39) and chronic (24-hour recovery; N=35) cohorts following 1-hour occlusion. Mice were treated with either vehicle or NTS-104 (N=4–6 animals per sex-, age-, and treatment-matched subgroup). Collateral flow, hemodynamics, and neutrophil aggregation were assessed by laser speckle contrast imaging and two-photon microscopy following cranial window surgery. All measurements were normalized to baseline. Additionally, to identify mechanisms underlying acute ischemia–recanalization injury, we performed transcriptomics analysis of peripheral blood samples collected from the acute cohort (N=17) compared to sham controls (N=16).
Immediately after recanalization, treatment improved blood flow and vessel diameter, particularly in female and young mice. At 24 hours post-recanalization, NTS-104 significantly increased cerebral blood flow and vessel diameter, specifically in female and aged mice. Transcriptomic analysis revealed enrichment of neutrophil-mediated pathways in females, and preliminary imaging suggests that NTS-104 reduces neutrophil aggregation. Collateral vessel flow was unaffected by treatment.
These findings demonstrate that NTS-104 enhances reperfusion and attenuates neutrophil-mediated microvascular obstruction post-recanalization, representing a promising vascular-protective therapy with more significant benefits in female and aged populations.