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

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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.

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References

  • Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96:12866–12869

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Andras IE, Pu H, Tian J, Deli MA, Nath A, Hennig B, Toborek M (2005) Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab 25:1159–1170

    Article  CAS  PubMed  Google Scholar 

  • Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR (2009) VEGF-mediated disruption of endothelial CLN-5 promotes blood–brain barrier breakdown. Proc Natl Acad Sci USA 106:1977–1982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barone F, White R, Spera P, Ellison J, Currie R, Wang X, Feuerstein G (1998) Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 29:1937–1950

    Article  CAS  PubMed  Google Scholar 

  • Bolton SJ, Anthony DC, Perry VH (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo. Neuroscience 86:1245–1257

    Article  CAS  PubMed  Google Scholar 

  • Candelario-Jalil E, Taheri S, Yang Y, Sood R, Grossetete M, Estrada EY, Fiebich BL, Rosenberg GA (2007) Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther 323:488–498

    Article  CAS  PubMed  Google Scholar 

  • Cardenas A, Moro MA, Leza JC, O’Shea E, Davalos A, Castillo J, Lorenzo P, Lizasoain I (2002) Upregulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance. J Cereb Blood Flow Metab 22:1297–1302

    Article  CAS  PubMed  Google Scholar 

  • Coisne C, Engelhardt B (2011) Tight junctions in brain barriers during central nervous system inflammation. Antioxid Redox Signal 15:1285–1303

    Article  CAS  PubMed  Google Scholar 

  • Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64:37–43

    Article  PubMed  Google Scholar 

  • Didier N, Romero IA, Creminon C, Wijkhuisen A, Grassi J, Mabondzo A (2003) Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem 86:246–254

    Article  CAS  PubMed  Google Scholar 

  • Fischer S, Wiesnet M, Marti HH, Renz D, Schaper W (2004) Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells. J Cell Physiol 198:359–369

    Article  CAS  PubMed  Google Scholar 

  • Fischer S, Wiesnet M, Renz D, Schaper W (2005) H2O2 induces paracellular permeability of porcine brain-derived microvascular endothelial cells by activation of the p44/42 MAP kinase pathway. Eur J Cell Biol 84:687–697

    Article  CAS  PubMed  Google Scholar 

  • Gesuete R, Orsini F, Zanier ER, Albani D, Deli MA, Bazzoni G, De Simoni MG (2011) Glial cells drive preconditioning-induced blood–brain barrier protection. Stroke 42:1445–1453

    Article  PubMed  Google Scholar 

  • Gu Z, Jiang Q, Zhang G (2001) Extracellular signal-regulated kinase and c-Jun N-terminal protein kinase in ischemic tolerance. Neuro Rep 12:3487–3491

    CAS  Google Scholar 

  • Hirt L, Ternon B, Price M, Mastour N, Brunet JF, Badaut J (2009) Protective role of early aquaporin 4 induction against postischemic edema formation. J Cereb Blood Flow Metab 29:423–433

    Article  CAS  PubMed  Google Scholar 

  • Ishrat T, Sayeed I, Atif F, Hua F, Stein DG (2010) Progesterone and allopregnanolone attenuate blood–brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol 226:183–190

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiao H, Wang Z, Liu Y, Wang P, Xue Y (2011) Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 44:130–139

    Article  CAS  PubMed  Google Scholar 

  • Karikó K, Weissman D, Welsh F (2004) Inhibition of toll-like receptor and cytokine signaling–a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 24:1288–1304

    Article  PubMed  Google Scholar 

  • Kondo T, Reaume AG, Huang TT, Carlson E, Murakami K, Chen SF, Hoffman EK, Scott RW, Epstein CJ, Chan PH (1997) Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci 17:4180–4189

    CAS  PubMed  Google Scholar 

  • Lange-Asschenfeldt C, Raval AP, Dave KR, Mochly-Rosen D, Sick TJ, Perez-Pinzon MA (2004) Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab 24:636–645

    Article  CAS  PubMed  Google Scholar 

  • Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD, McCullough LD (2004) Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol 187:94–104

    Article  PubMed  Google Scholar 

  • Lin TN, He YY, Wu G, Khan M, Hsu CY (1993) Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24:117–121

    Article  CAS  PubMed  Google Scholar 

  • Liu HQ, Li WB, Li QJ, Zhang M, Sun XC, Feng RF, Xian XH, Li SQ, Qi J, Zhao HG (2006) Nitric oxide participates in the induction of brain ischemic tolerance via activating ERK1/2 signaling pathways. Neurochem Res 31:967–974

    Article  CAS  PubMed  Google Scholar 

  • Masada T, Hua Y, Xi G, Ennis SR, Keep RF (2001) Attenuation of ischemic brain edema and cerebrovascular injury after ischemic preconditioning in the rat. J Cereb Blood Flow Metab 21:22–33

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Shudou M, Ii C, Takahashi H, Imai Y, Tanaka J (2007) Antibodies to CD11b, CD68, and lectin label neutrophils rather than microglia in traumatic and ischemic brain lesions. J Neurosci Res 85:994–1009

    Article  CAS  PubMed  Google Scholar 

  • Meller R, Simon RP (2013) Tolerance to Ischemia - an increasingly complex biology. Transl Stroke Res 4:40–50

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miao B, Yin XH, Pei DS, Zhang QG, Zhang GY (2005) Neuroprotective effects of preconditioning ischemia on ischemic brain injury through down-regulating activation of JNK1/2 via N-methyl-D-aspartate receptor-mediated Akt1 activation. J Biol Chem 280:21693–21699

    Article  CAS  PubMed  Google Scholar 

  • Narayanan SV, Dave KR, Perez-Pinzon MA (2013) Ischemic preconditioning and clinical scenarios. Curr Opin Neurol 26:1–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park JS, Shin JA, Jung JS, Hyun JW, Van Le TK, Kim DH, Park EM, Kim HS (2012) Anti-inflammatory mechanism of compound K in activated microglia and its neuroprotective effect on experimental stroke in mice. J Pharmacol Exp Ther 341:59–67

    Article  CAS  PubMed  Google Scholar 

  • Sandoval KE, Witt KA (2008) Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32:200–219

    Article  CAS  PubMed  Google Scholar 

  • Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86:1659–1669

    Article  CAS  PubMed  Google Scholar 

  • Shamloo M, Rytter A, Wieloch T (1999) Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning. Neuroscience 93:81–88

    Article  CAS  PubMed  Google Scholar 

  • Shen F, Walker EJ, Jiang L, Degos V, Li J, Sun B, Heriyanto F, Young WL, Su H (2011) Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood–brain barrier and reduces atrophy volume. J Cereb Blood Flow Metab 31:2343–2351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shin JA, Park EM, Choi JS, Seo SM, Kang JL, Lee KE, Cho S (2009) Ischemic preconditioning-induced neuroprotection is associated with differential expression of IL-1beta and IL-1 receptor antagonist in the ischemic cortex. J Neuroimmunol 217:14–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shin JA, Choi JH, Choi YH, Park EM (2011) Conserved aquaporin 4 levels associated with reduction of brain edema are mediated by estrogen in the ischemic brain after experimental stroke. Biochim Biophys Acta 1812:1154–1163

    Article  CAS  PubMed  Google Scholar 

  • Stamatovic SM, Keep RF, Andjelkovic AV (2008) Brain endothelial cell–cell junctions: how to “open” the blood–brain barrier. Curr Neuropharmacol 6:179–192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stanimirovic D, Satoh K (2000) Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 10:113–126

    Article  CAS  PubMed  Google Scholar 

  • Takahashi E, Niimi K, Itakura C (2009) Motor coordination impairment in aged heterozygous rolling Nagoya, Cav2.1 mutant mice. Brain Res 1279:50–57

    Article  CAS  PubMed  Google Scholar 

  • Valable S, Montaner J, Bellail A, Berezowski V, Brillault J, Cecchelli R, Divoux D, Mackenzie ET, Bernaudin M, Roussel S, Petit E (2005) VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. J Cereb Blood Flow Metab 25:1491–1504

    Article  CAS  PubMed  Google Scholar 

  • Wang ZQ, Wu DC, Huang FP, Yang GY (2004) Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res 996:55–66

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Xue Y, Jiao H, Liu Y, Wang P (2012) Doxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctions and PKCdelta signaling in rats. J Mol Neurosci 47:89–100

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    Article  CAS  PubMed  Google Scholar 

  • Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M (2002) Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379–392

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Park TS, Gidday JM (2007) Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am J Physiol Heart Circ Physiol 292:H2573–H2581

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2011-0015923 and 2012R1A5A2A32671867).

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The authors report no conflicts of interest.

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Authors and Affiliations

  1. 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

    Jin A. Shin, Sae Im Jeong & Eun-Mi Park

  2. Department of Pharmacology, School of Medicine, Ewha Womans University, 911-1 Mok6dong Yangcheon-gu, Seoul, 158-710, Republic of Korea

    Yul A. Kim & Kyung-Eun Lee

  3. Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea

    Hee-Sun Kim

  4. Department of Brain & Cognitive Sciences, Brain Disease Research Institute, Ewha Womans University, 52, Ewhayeodae-gil Seodaemun-gu, Seoul, 120-750, Republic of Korea

    Hee-Sun Kim & Eun-Mi Park

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  1. Jin A. Shin
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Correspondence to Eun-Mi Park.

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Shin, J.A., Kim, Y.A., Jeong, S.I. et al. Extracellular signal-regulated kinase1/2-dependent changes in tight junctions after ischemic preconditioning contributes to tolerance induction after ischemic stroke. Brain Struct Funct 220, 13–26 (2015). https://doi.org/10.1007/s00429-013-0632-5

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  • DOI: https://doi.org/10.1007/s00429-013-0632-5

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