Oxidative Stress and Mitochondrial Dysfunction in Neurovascular Injury after Stroke(<SPECIAL ISSUE>Neuroscience for the Development of Neurosurgery in the Near Futre)

抄録

Effective stroke therapies require recanalization of occluded cerebral blood vessels. However, reperfusion can cause neurovascular injury, leading to cerebral edema, brain hemorrhage, and neuronal death by apoptosis/necrosis. These complications of reperfusion, which result from excess production of reactive oxygen species (ROS), significantly limit the benefits of stroke therapies. We recently found two novel targets for neurovascular protection after ischemia/reperfusion: the signal transducer and activator of transcription 3 (STAT3) pathway and NADPH oxidase (NOX). Manganese-superoxide dismutase (SOD2) plays a critical role in neurovascular injury as a first-line defense against ROS produced in mitochondria, and STAT3 is a major transcriptional factor of the SOD2 gene. During reperfusion, activation of STAT3 and its recruitment into the SOD2 gene are blocked, resulting in increased oxidative stress and neuronal apoptosis. Pharmacological activation of STAT3 with interleukin-6 induces SOD2 expression, which limits ischemic neuronal death. In contrast, NOX is a pro-oxidant multi-subunit enzyme. After ischemia/reperfusion, NOX in the neurovascular unit forms an activated complex to generate ROS, which induce oxidative injury in the neurovascular unit. Pharmacological and genetic inhibition of NOX is neuroprotective against cerebral ischemia/reperfusion. Superoxide dismutase and NOX regulate ROS production in the ischemic brain, interacting with each other in a Yin and Yang relationship. Our neurovascular protective strategies targeting these two enzymes may expand the therapeutic window of the currently approved therapies.