Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation

Redox Biology
Tuo YangFeng Zhang

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.

Citations

May 24, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lixuan ZhanEn Xu
Oct 23, 2019·Journal of Internal Medicine·P StenvinkelB Natterson-Horowitz
Feb 20, 2019·Frontiers in Pharmacology·Andrea Rodrigues VasconcelosCarolina Demarchi Munhoz
Mar 6, 2021·Cellular and Molecular Neurobiology·Qianqian LiFeng Zhang
Jul 1, 2021·The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology·Yuefang LiXin Hu
Aug 14, 2021·Acta Pharmaceutica Sinica. B·Chenglong GaoTao Pang

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Methods Mentioned

BETA
electrophoresis
PCR
X-ray
dot blot
transfection
nuclear translocation
dot blots
immunoprecipitation
ubiquitination

Software Mentioned

PCR Array Data Analysis
NIH Image J
ARRIVE

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