Mechanisms and Therapeutic Targets of Ischemia—Reperfusion Injury in Stroke: A Narrative Review Focusing on Blood—Brain Barrier Dysfunction

Ischemic stroke remains a leading cause of death and disability worldwide. While thrombolysis and endovascular thrombectomy are current mainstays of treatment, their clinical efficacy is often undermined by ischemia-reperfusion injury (I/R). This injury induces secondary brain damage, primarily via disruption of the blood-brain barrier (BBB). No approved therapies directly target BBB protection. This review reinterprets the pathophysiological mechanism of BBB disruption after stroke through a dynamic spatiotemporal framework. The pathological cascade reaction is clearly divided into two core stages: the ischemic phase is mainly driven by energy failure and calcium overload; the reperfusion phase is further divided into four consecutive and progressive sub-stages, namely, oxidative stress burst, amplification of inflammatory response, matrix metalloproteinase 9 (MMP-9)-mediated barrier degradation and programmed cell death. This review critically assesses current therapies and identifies major clinical translation gaps, including a temporal mismatch between preclinical and clinical windows, unacceptable toxicity, lack of durable efficacy and biphasic effects. Matching specific interventions to the different pathophysiological stages of blood-brain barrier disruption is essential for optimizing clinical outcomes.