Immune modulatory and vascular protective effects of Ibudilast in post-stroke inflammation

Ischemic stroke induces sustained microvascular dysfunction and inflammation, contributing to futile recanalization and poor tissue recovery despite successful large-vessel reopening. Neutrophil adhesion and capillary stalling are key drivers of this microvascular failure. While Ibudilast, a small-molecule phosphodiesterase (PDE3/4) inhibitor with vasodilatory and anti-inflammatory properties, has shown promise in modulating neuroinflammation, its impact on post-stroke microvascular flow and neutrophil-mediated obstruction remains poorly understood. In this study, we investigated the effects of Ibudilast on cerebral perfusion, neutrophil dynamics, and infarct size following transient middle cerebral artery occlusion (MCAO) in young (4-6 months) and aged (18-20 months) male and female C57BL/6 mice, a design intended to reflect clinically relevant variability in stroke outcomes. Ibudilast (30 mg/kg, intraperitoneally) was administered at 30 min and 6 h post-occlusion, and in vivo imaging was performed at 3hPR and 24hPR to assess hemodynamic parameters and neutrophil behavior. Treatment preserved vessel diameter, maintained flow velocity, restored red blood cell flux, and enhanced perfusion in both surface and capillary compartments, with improvements most pronounced in young and female cohorts. Neutrophil adhesion and capillary stalling were reduced. In vehicle-treated animals, neutrophil stalls correlated strongly with impaired vascular flow, whereas this relationship was absent in the treated group. These microvascular improvements were accompanied by a significant reduction in infarct volume (>50 %) at 24hPR compared to vehicle-treated controls. Together, these findings highlight Ibudilast's therapeutic potential for preserving microvascular integrity and guiding adjunctive interventions to mitigate futile recanalization in acute ischemic stroke.