Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation
DOI
10.1016/j.redox.2018.05.001
Document Type
Journal Article
Publication Date
7-1-2018
Publication Title
Redox Biology
Volume
17
First Page
323
Last Page
337
ISSN
22132317
Keywords
Conditioning, Electrophile, Ischemic tolerance, Lipid peroxidation, Neuroprotection, Stroke, VE-cadherin
Abstract
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation.
Open Access
Gold
Repository Citation
Yang, T., Sun, Y., Mao, L., Zhang, M., Li, Q., Zhang, L., Shi, Y., Leak, R., Chen, J., & Zhang, F. (2018). Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation. Redox Biology, 17, 323-337. https://doi.org/10.1016/j.redox.2018.05.001