Targeting Reperfusion Injury in the Age of Mechanical Thrombectomy.

Abstract

Pharmacological recanalization with r-tPA (recombinant tissue-type plasminogen activator) has been the mainstay for acute ischemic stroke (IS) treatment.1 Recent randomized controlled trials have additionally demonstrated the efficacy of mechanical thrombectomy (MT).2–4 Although the restoration of blood flow is a major goal in acute treatment, if this occurs too late, worse damage can ensue, compared with no revascularization.5 This worsening results because of the generation of excess reactive oxygen species (ROS) which leads to direct cellular damage and indirect damage through the triggering of inflammation. Inflammation causes the generation of damaging immune mediators, effector molecules, and more ROS.6 ROS can also lead to apoptosis/necrosis via DNA/RNA damage and lipid peroxidation. This cycle is known as reperfusion injury (R/I; Figure). Experimental studies have shown that durations of >2- to 3-hours transient middle cerebral artery occlusion (tMCAO) lead to worsened injury compared with permanent MCAO.7 At the clinical level, delayed revascularization can sometimes lead to worsened outcomes.8 Hyperintense acute reperfusion marker seen on magnetic resonance imaging in some patients with stroke has been associated with hemorrhagic transformation (HTf) and clinical worsening, suggesting the existence of R/I in humans.9 Hence, adjunctive treatments to recanalization to target R/I has the potential to improve current outcomes while reducing complications of r-tPA. Figure. Reperfusion injury is thought to occur when a sudden influx of oxygenated blood introduces reactive oxygen species (ROS) into critically damaged ischemic brain. Ischemically damaged mitochondria become unable to efficiently neutralize ROS. Elevated ROS can directly damage DNA, RNA, and cause lipid peroxidation. ROS lead to immune cell activation, including brain resident microglia. Ischemic brain may also elaborate damage-associated molecular patterns (DAMPs) that act on Toll-like receptors (TLR) present on the surface of microglia. TLR activation triggers immune …