Abstract
Ischemic stroke is one of the leading causes of death and long-term disability worldwide; however, effective clinical approaches are still limited. The transcriptional factor Nrf2 is a master regulator in cellular and organismal defense against endogenous and exogenous stressors by coordinating basal and stress-inducible activation of multiple cytoprotective genes. The Nrf2 network not only tightly controls redox homeostasis but also regulates multiple intermediary metabolic processes. Therefore, targeting Nrf2 has emerged as an attractive therapeutic strategy for the prevention and treatment of CNS diseases including stroke. Here, the current understanding of the Nrf2 regulatory network is critically examined to present evidence for the contribution of Nrf2 pathway in rodent ischemic stroke models. This review outlines the literature for Nrf2 studies in preclinical stroke and focuses on the in vivo evidence for the role of Nrf2 in primary and secondary brain injuries. The dynamic change and functional importance of Nrf2 signaling, as well as Nrf2 targeted intervention, are revealed in permanent, transient, and global cerebral ischemia models. In addition, key considerations, pitfalls, and future potentials for Nrf2 studies in preclinical stroke investigation are discussed.
Highlights
Ischemic stroke is one of the leading causes of death and long-term disability worldwide (Benjamin et al, 2018), an event which is more disabling than it is fatal
Nrf2 Mechanism permanent distal MCA occlusion (pdMCAO) Findings supporting the role of Nrf2 pathway
Changes are absent in Nrf2−/− mice
Summary
Ischemic stroke is one of the leading causes of death and long-term disability worldwide (Benjamin et al, 2018), an event which is more disabling than it is fatal. When cells are exposed to excessive oxidative stimuli during cerebral ischemia, Nrf2 is liberated from Keap1, translocates into the nucleus, and binds to the ARE sequence, thereby upregulating the expression of its target genes, which code cytoprotective proteins like anti-oxidative enzymes.
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