Stroke Reperfusion Injury

Excerpt

Stroke is a significant cause of mortality and disability worldwide, which affects about 2.5% of the global population. The ischemic core, the most proximal part of the arterio-vascular occlusion, sustains maximal damage during a stroke. Between the ischemic core and healthy brain tissue resides the "penumbra," characterized by mild-to-moderate hypoxia. This area risks irreversible damage without restoring blood flow to normal levels within a critical period. Without therapeutic interventions and continued ischemia, the loss of brain tissue can be staggering, with an estimated decline of 1.9 million neurons, 14 billion synapses, and 12 km of myelinated fibers every minute.

Specifically, 1 hour of ischemic brain damage equals 3.6 years of normal brain aging. Acute stroke therapeutics target the tissue damage occurring at the penumbra level and restore the penumbra's functionality. Alteplase, a tissue plasminogen activator (tPA), is the only clot-busting medication approved by the United States Food and Drug Administration (FDA) and recanalizes thrombosed/occluded vasculature in ischemic stroke cases. Many studies consistently demonstrate improved outcomes in acute ischemic stroke (AIS) patients treated with tPA. However, interventions such as newer proven endovascular techniques such as mechanical thrombectomy aimed at recanalizing thrombosed vessels, when combined with tPA, may paradoxically result in detrimental effects on ischemic tissue due to complex biochemical and pathological events. In a subacute context, procedures such as carotid endarterectomy and stenting may also lead to reperfusion injury. Such functional, microscopic, and sometimes macroscopic injury consequential to blood flow restoration is termed an ischemia-reperfusion injury (IRI).

IRI presents a clinical challenge characterized by the exacerbation of cellular dysfunction and death upon restoration of blood flow to previously ischemic tissues. Despite the necessity of restoring blood flow to salvage ischemic tissues, reperfusion paradoxically induces further damage, thereby impeding the function and viability of the affected organ. This phenomenon is observed across various organs, including the heart, lungs, kidneys, gut, skeletal muscles, and brain. Furthermore, IRI may extend beyond the primary ischemic site, triggering systemic damage that culminates in multisystem organ failure. The multifaceted nature of reperfusion injury involves intricate molecular and cellular mechanisms, culminating in extensive tissue destruction.