Phased blood-brain barrier disruption in ischaemic stroke: implications for therapy?

Abstract

Cerebrovascular disease, which primarily affects the brain's blood vessels, remains a major global cause of death and disability. Among its clinical manifestations, ischaemic stroke is by far the most common. Prolonged oedema due to blood vessel leakage is detrimental to the delicate neuronal environment throughout the ischaemic and reperfusion phase and contributes to the mortality, morbidity, and disabilities associated with this devastating condition. Under physiological conditions, an intact blood-brain barrier (BBB) protects and regulates solute and cell transit in and out of the central nervous system. Indeed, dysfunction of this formidable cerebrovascular regulator has been functionally linked to adverse outcomes in stroke. While our knowledge of the underlying mechanism is incomplete, increasing evidence, particularly from studies using models of rodents exposed to middle cerebral artery occlusion (MCAO), supports a biphasic breakdown of the BBB in ischemic stroke. However, debate persists regarding the precise mechanisms of BBB dysfunction. Understanding this pathobiology is essential for developing targeted interventions to improve clinical outcomes in stroke patients. In this review, we provide a summary of the structure and function of the BBB as well as the cellular and molecular determinants of leakage pathways present in pathological conditions, and evaluate medical strategies aimed at reducing BBB disruption in stroke. We also discuss the potential for selectively targeting specific phases of BBB leakage.