title: 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.
authors.affiliation: Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, 911-1 Mok6dong Yangcheon-gu, Seoul, 158-710, Republic of Korea.
authors.forename: Jin A
authors.initials: JA
authors.lastname: Shin
authors.forename: Yul A
authors.initials: YA
authors.lastname: Kim
authors.forename: Sae Im
authors.initials: SI
authors.lastname: Jeong
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000209:etiology; D020520:Brain Infarction / Q000209:etiology; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D053580:Muscle Strength / Q000187:drug effects; D009460:Neurologic Examination; D009570:Nitriles / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3