Beyond Reperfusion: Adjunctive Therapies Targeting Inflammation, Edema, and BBB Dysfunction in Ischemic Stroke.

Background: Stroke remains a leading cause of disability and death worldwide. While reperfusion therapies such as tissue plasminogen activator (tPA) and mechanical thrombectomy have significantly improved stroke management, their effectiveness is limited by ischemia/reperfusion (I/R) injury, which disrupts the blood-brain barrier, increases neuroinflammation, and exacerbates secondary neuronal damage. Consequently, there is an urgent need for adjunctive therapies that specifically target these secondary injury mechanisms.

Summary: This review explores novel therapeutic strategies aimed at mitigating neuroinflammation, post-stroke edema, and BBB permeability. Key approaches discussed include anti-inflammatory therapies targeting tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinases (MMPs); neuromodulation by vagus nerve stimulation (VNS); and the inhibition of edema-related molecules such as sulfonylurea receptor 1 (SUR1), aquaporin-4 (AQP4), and both systemic and peripheral hypothermic cooling. While these therapies show promise in preclinical models, their clinical translation is hindered by challenges such as systemic immunosuppression, susceptibility to infection, and limited therapeutic windows. Among these therapies assessed, SUR1 inhibition and Remote Administration of Hypothermia (RAH) are promising candidates for improving stroke outcomes.

Key messages: Secondary injury from BBB disruption, inflammation, and edema remains a major barrier to optimal stroke recovery. Pharmacologic, neuromodulatory, and molecular-targeting strategies- including TNF-a, IL-6, MMP inhibition, VNS, and hypothermia, each offer distinct therapeutic mechanisms, but face critical clinical translation barriers Among emerging therapies, Remote administration of hypothermia (RAH) and SUR1 inhibition represent novel interventions that address many of the translational challenges of other therapies by addressing key mechanisms of neuroinflammation and edema with favorable safety profiles.