Extracellular signal-regulated kinase1/2-dependent changes in tight junctions after ischemic preconditioning contributes to tolerance induction after ischemic stroke

Abstract

Less disruption of the blood-brain barrier (BBB) after severe ischemic stroke is one of the beneficial outcomes of ischemic preconditioning (IP). However, the effect of IP on tight junctions (TJs), which regulate paracellular permeability of the BBB, is not well understood. In the present study, we examined IP-induced changes in TJs before and after middle cerebral artery occlusion (MCAO) in mice, and the association between changes in TJs and tolerance to a subsequent insult. After IP, we found decreased levels of transmembrane TJ proteins occludin and claudin-5, and widened gaps of TJs with perivascular swelling at the ultrastructural level in the brain. An inflammatory response was also observed. These changes were reversed by inhibition of extracellular signal-regulated kinase1/2 (ERK1/2) via the specific ERK1/2 inhibitor U0126. After MCAO, reduced brain edema and inflammatory responses were associated with altered levels of angiogenic factors and cytokines in preconditioned brains. Pretreatment with U0126 reversed the neuroprotective effects of IP against MCAO. These findings suggest that ERK1/2 activation has a pivotal role in IP-induced changes in TJs and inflammatory response, which serve to protect against BBB breakdown and inflammation after ischemic stroke.

Bacterial induction of Snail1 contributes to blood-brain barrier disruption

“…Second, the JNKs and third, p38, respond to different types of cellular stress and inflammatory mediators (50). Activation of ERK1/2 results in increased ZO-1 degradation during traumatic brain injury (51), decreased ZO-1 and claudin 5 expression in brain endothelium during HIV infection (52,53), and reduced occludin and claudin 5 expression in BBB endothelium during ischemic stroke (54). Whether Snail1 is similarly involved in tight junction disruption under these conditions remains to be determined.…”

Selective knockout of astrocytic Na+/H+ exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke

“…TJ transmembrane proteins, such as occludin and claudin-5 or Zo-1, play a key role in the functional preservation of the BBB (Bazzoni et al, 2000;Hawkins & Davis 2005). As astrocyte endfeet cover over 95% of the brain capillary surface, the swelling of astrocyte endfeet causes disassembly of the tight junction network and decreased expression of TJ proteins such as occludin and claudin-5 (Shin et al, 2015;Willis, Leach, Clarke, Nolan, & Ray, 2004). In this study, we observed extensive EB extravasation into brain parenchyma in the IL hemispheres of the control mouse brains, indicating vascular leakage.…”

Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

“…A 5-point graded scoring system for neurological scores and the wire suspension test was used (Shin et al, 2015). Forelimb strength was measured with the Grip strength tester bio-GS3 (BIOSEB, Virtolles cedex, France) prior to and 3 days after MCAO.…”