Ischemic stroke: molecular mechanisms of blood-brain barrier dysfunction and opportunities for drug development

Ischemic stroke remains a leading cause of disability and death, yet decades of therapeutic development have yielded remarkably little clinical progress. The limited progress in improving stroke outcomes is closely linked to dysfunction of the blood-brain barrier (BBB), which undergoes profound structural and functional disruption during ischemic injury. Barrier injury under ischemic conditions is driven, in part, by glutamate dysregulation, neuroinflammation, and oxidative stress, which act in concert to destabilize endothelial integrity and exacerbate BBB permeability. Targeting these interconnected mechanisms represents a promising approach to preserve BBB function and limit secondary injury following stroke. Interventions aimed at modulating excitotoxic signaling, inflammatory cascades, and redox imbalance can protect the BBB and the larger neurovascular unit (NVU); however, aging further compromises BBB integrity and resilience, compounding these pathological processes and posing additional challenges for therapeutic development, particularly given the higher incidence of stroke in older individuals. This review highlights current understanding of BBB physiology in health and under ischemic conditions with an emphasis on how excitotoxicity, neuroinflammation, and oxidative stress compromise BBB functional integrity. Additionally, we evaluate therapeutic strategies aimed at preserving or restoring BBB homeostasis. By integrating insights into BBB biology with advances in neurovascular therapeutics, this review provides a forward-thinking assessment on the future of therapeutic development for ischemic stroke.