Oxidative stress and mitochondrial dysfunction in neurovascular injury after stroke

Hideyuki Yoshioka, Hiroyuki Sakata, Nobuya Okami, Hiroyuki Kinouchi, Pak H. Chan

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 (S0D2) 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-supunit 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.

Original languageEnglish
Pages (from-to)559-565
Number of pages7
JournalJapanese Journal of Neurosurgery
Volume20
Issue number8
DOIs
Publication statusPublished - 2011 Nov

Keywords

  • Cerebral ischemia
  • NADPH oxidase
  • Reactive oxygen species
  • STAT3
  • Superoxide dismutase

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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