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

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.

Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway

“…Previous in vivo and vitro studies have shown that Nrf‐2 protein expression decreased after oxidative damage . Our findings are consistent with previous researches, but some studies have suggested that Nrf‐2 had transported into the nucleus after ischemia and its expression increased . These discrepancies in mechanism may be due to the use of different animal species and models of ischemic stroke, as well as variations in sampling time points and parts.…”

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges

“…However, current research perspectives regard that there is usually an unprotected window with little or no neuroprotection between the first window and the second window (104). Recent research evidence suggests that repeated hypoxic preconditioning can even mediate brain tissue to produce a third protective window that lasts up to 8 weeks of which the underlying mechanism may be caused by epigenetic regulation (106,107).…”

“…The transmembrane TJs and AJs are mainly composed of claudin-5 and cadherin 5, which are involved in regulating paracellular permeability (201). IPreC can maintain the BBB permeability by directly upregulating the TJs protein claudin 5 and the AJ protein cadherin 5 (109,203) IPreC-induced cytokines, such as TNF-α and interleukin 1β (IL-1β), may affect BBB permeability (106). IPreC can mediate TJs and angiogenic factors levels via activating ERK1/2, implying an essential role of ERK1/2 in paracellular permeability in IPreC (106).…”

“…IPreC can maintain the BBB permeability by directly upregulating the TJs protein claudin 5 and the AJ protein cadherin 5 (109,203) IPreC-induced cytokines, such as TNF-α and interleukin 1β (IL-1β), may affect BBB permeability (106). IPreC can mediate TJs and angiogenic factors levels via activating ERK1/2, implying an essential role of ERK1/2 in paracellular permeability in IPreC (106). Other studies showed that the underlying mechanisms of IPreC-mediated BBB protection involve VEGF, Nrf2, or inflammatory pathways (109,201).…”

Biomimetics – Nature's roadmap to insights and solutions for burden of lifestyle diseases

“…As we lack potent treatments to block effects of ischaemia and hypoxia in medicine, mammalian models that help us to better understand tolerance against hypoxia‐anoxia are meaningful. Brain ischaemic preconditioning protects against ischaemic injury via oxidative signalling and Nrf2‐KEAP1 activation . Thus, nutrients and drugs that stimulate Nrf2‐KEAP1 should be tested in conditions with tissue hypoxia .…”