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.