Review identifies key mechanisms and therapeutic targets for ischemia-reperfusion injury in stroke, focusing on blood-brain barrier dysfunction

Ischemic stroke is a leading cause of death and disability globally, characterized by vascular occlusion leading to neuronal injury. While revascularization therapies like thrombolysis and thrombectomy restore blood flow, many patients suffer from cerebral ischemia-reperfusion injury (CIRI). This secondary injury exacerbates outcomes through blood-brain barrier (BBB) disruption, oxidative stress, and neuroinflammation. Current interventions for CIRI are limited, underscoring a critical unmet need for targeted strategies to protect the BBB and mitigate post-reperfusion damage.

This work is a narrative review that systematically synthesized existing literature on the complex molecular mechanisms underlying cerebral ischemia-reperfusion injury (CIRI) in stroke. The authors focused specifically on pathophysiological processes contributing to blood-brain barrier (BBB) dysfunction following cerebral ischemia and reperfusion. The review aimed to identify and discuss various mechanisms, including oxidative stress, inflammation, and cell death pathways, to pinpoint potential therapeutic targets for CIRI prevention and treatment.

The review elucidated that CIRI involves a cascade of detrimental processes, collectively compromising BBB integrity and function. Key mechanisms identified include the overproduction of reactive oxygen species (ROS), acidosis, calcium dysregulation, and the activation of inflammatory and regulated cell death pathways. These processes synergistically exacerbate BBB disruption, neuroinflammation, and apoptosis. Specifically, the review highlighted how oxidative stress, ferroptosis, and inflammatory responses contribute to membrane damage.

The collective action of ROS overproduction, acidosis, calcium dysregulation, and activation of inflammatory and regulated cell death pathways significantly worsens BBB disruption and neuronal outcomes in CIRI.