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Abdullah, Zuraidah; Bayraktutan, Ulvi (2014)
Publisher: Elsevier
Languages: English
Types: Article
The pro-inflammatory cytokine TNF-α severely perturbs the integrity of the blood–brain barrier (BBB). This study explored the specific roles of NADPH oxidase and associated downstream effectors by using human brain microvascular endothelial cells (HBMECs) and human astrocytes (HAs), the key components of BBB, alone or in co-cultures to mimic human BBB. Exposure to TNF-α (6 h) impaired BBB integrity as evidenced by marked decreases in transendothelial electrical resistance and concurrent increases in paracellular flux which appeared to subside with time (24 h). Increased barrier dysfunction concurred with increases in endothelial NADPH oxidase activity, O2radical dot− production, actin stress fibre formation, MMP-2/9 activities and concomitant decreases in antioxidant (CuZn-SOD and catalase) and tight junction (claudin-5 and occludin) protein expressions. Conversely, TNF-α did not affect astrocytic MMP activities and antioxidant enzyme expressions. Unlike BBB damage, rates of HBMEC and HA apoptosis increased by time. Suppression of NADPH oxidase by apocynin or diphenyleneiodonium prevented TNF-α-evoked morphological changes and apoptosis, attenuated endothelial MMP activity and helped retain usual tight junction protein expression and barrier function. In conclusion, HBMECs constitute the main source of oxidative stress and basement-membrane degrading endopeptidases in inflammatory conditions associated with excessive release of TNF-α where targeting NADPH oxidase may prove extremely beneficial in maintaining proper barrier activity through prevention of cytoskeletal and tight junction reorganisations.
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    • Abdullah, Z., Bayraktutan, U., 2014. NADPH oxidase mediates TNF-alpha-evoked in vitro brain barrier dysfunction: roles of apoptosis and time. Mol. Cell. Neurosci. 61, 72-84.
    • Allen, C., Srivastava, K., Bayraktutan, U., 2010. Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction. Stroke.
    • Allen, C.L., Bayraktutan, U., 2009. Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood-brain barrier hyperpermeability. Diabetes, Obes. Metab. 11, 480-490.
    • Ballabh, P., Braun, A., Nedergaard, M., 2004. The blood-brain barrier: an overview: Structure, regulation, and clinical implications. Neurobiol. Dis. 16, 1-13.
    • Barone, F.C., Arvin, B., White, R.F., Miller, A., Webb, C.L., Willette, R.N., Lysko, P.G., Feuerstein, G.Z., 1997. Tumor Necrosis Factor-α : A Mediator of Focal Ischemic Brain Injury. Stroke 28, 1233-1244.
    • Basuroy, S., Bhattacharya, S., Tcheranova, D., Qu, Y., Regan, R.F., Leffler, C.W., Parfenova, H., 2006. HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells. Am. J. of Physiol. Cell Physiol. 291, C897-C908.
    • Bauer, A.T., Burgers, H.F., Rabie, T., Marti, H.H., 2010. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J. Cereb. Blood Flow Metab. 30, 837-848.
    • Bayraktutan, U., 2002. Free radicals, diabetes and endothelial dysfunction. Diabetes, Obes. Metab. 4, 224-238.
    • Bresgen, N., Jaksch, H., Bauer, H.-C., Eckl, P., Krizbai, I., Tempfer, H., 2006. Astrocytes are more resistant than cerebral endothelial cells toward geno- and cytotoxicity mediated by short-term oxidative stress. J. Neurosci. Research 84, 1821-1828.
    • Candelario-Jalil, E., Yang, Y., Rosenberg, G.A., 2009. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158, 983-994.
    • Chen, H., Kim, G.S., Okami, N., Narasimhan, P., Chan, P.H., 2011. NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol. Dis. 42, 341-348.
    • Chen, H., Song, Y.S., Chan, P.H., 2009. Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 29, 1262-1272.
    • Chen, Y., Swanson, R.A., 2003. Astrocytes and Brain Injury. J. Cereb. Blood Flow Metab. 23, 137-149.
    • Cotrina, M.L., Lin, J.H., Nedergaard, M,. 1998. Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J. Neurosci. 18, 8794-8804.
    • Dejana, E., 2004. Endothelial cell-cell junctions: happy together. Nat. Rev. Mol. Cell Biol. 5, 261-270.
    • Del Zoppo, G.J., Milner, R., Mabuchi, T., Hung, S., Wang, X., Berg, G.I., Koziol, J.A., 2007. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke. 38, 446-451.
    • Duan, S., Anderson, C.M., Stein, B.A., Swanson, R.A., 1999. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 19, 10193-10200.
    • Farrall, A.J., Wardlaw, J.M., 2009. Blood-brain barrier: Ageing and microvascular disease - systematic review and meta-analysis. Neurobiol. aging 30, 337-352.
    • Ferrarese, C., Mascarucci, P., Zoia, C., Cavarretta, R., Frigo, M., Begni, B., Sarinella, F., Frattola, L., De Simoni, M.G., 1999. Increased Cytokine Release From Peripheral Blood Cells After Acute Stroke. J. Cereb. Blood Flow Metab. 19, 1004-1009.
    • Fujimura, M., Gasche, Y., Morita-Fujimura, Y., Massengale, J., Kawase, M., Chan, P.H., 1999. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 842, 92-100.
    • Gao, X., Zhang, H., Belmadani, S., Wu, J., Xu, X., Elford, H., Potter, B.J., Zhang, C., 2008. Role of TNF-α-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. American Journal of Physiology-Heart Circ. Physiol. 295, H2242- H2249.
    • Gibson, C.L., Srivastava, K., Sprigg, N., Bath, P.M.W., Bayraktutan, U., 2014. Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. J. Neurochem.129, 816-826.
    • Giffard, R.G., Swanson, R.A., 2005. Ischemia-induced programmed cell death in astrocytes. Glia 50, 299-306.
    • Gu, X., Zhang, J., Brann, D.W., Yu, F.S.X., 2003. Brain and Retinal Vascular Endothelial Cells with Extended Life Span Established by Ectopic Expression of Telomerase. Invest. Ophthalmol. Vis. Sci. 44, 3219-3225.
    • Hansson, E., 2015, Actin Filament Reorganization in Astrocyte Networks is a Key Functional Step in Neuroinflammation Resulting in Persistent Pain: Novel Findings on Network Restoration. Neurochem. Res. 40, 372-379.
    • Hasturk, A., Atalay, B., Calisaneller, T., Ozdemir, O., Oruckaptan, H., Altinors, N., 2009. Analysis of Serum Pro-Inflammatory Cytokine Levels after Rat Spinal Cord Ischemia/Reperfusion Injury and Correlation with Tissue Damage. Turk. Neurosurg. 19, 353-359.
    • Hayashi, K., Nakao, S., Nakaoke, R., Nakagawa, S., Kitagawa, N., Niwa, M., 2004. Effects of hypoxia on endothelial/pericytic co-culture model of the blood-brain barrier. Regul. Peptides 123, 77-83.
    • Haydon, P.G., 2001, Glia: listening and talking to the synapse. Nat. Rev. Neurosci. 2, 185-193.
    • Heo, J.H., Lucero, J., Abumiya, T., Koziol, J.A., Copeland, B.R., del Zoppo, G.J. 1999. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624-633.
    • Hosomi, N., Ban, C.R., Naya, T., Takahashi, T., Guo, P., Song, X.y.R., Kohno, M., 2005. Tumor necrosis factor-[alpha] neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 25, 959-967.
    • Hurwitz, A.A., Berman, J.W., Rashbaum, W.K., Lyman, W.D., 1993. Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells. Brain Res. 625, 238-243.
    • Kahles, T., Luedike, P., Endres, M., Galla, H.J., Steinmetz, H., Busse, R., Neumann-Haefelin, T., Brandes, R.P., 2007. NADPH Oxidase Plays a Central Role in Blood-Brain Barrier Damage in Experimental Stroke. Stroke 38, 3000-3006.
    • Kim, J.A., Tran, N.D., Wang, S.-J., Fisher, M.J., 2003. Astrocyte regulation of human brain capillary endothelial fibrinolysis. Thromb. Res. 112, 159-165.
    • Kontos, H.A., 2001. Oxygen Radicals in Cerebral Ischemia: The 2001 Willis Lecture. Stroke 32, 2712-2716.
    • Krupinski, J., Lopez, E., Marti, E., Ferrer, I., 2000. Expression of Caspases and Their Substrates in the Rat Model of Focal Cerebral Ischemia. Neurobiol. Dis. 7, 332-342.
    • Li, G.Z., Wang, Z.H., Cui, W., Fu, J.L., Wang, Y.R., Li, U.P., 2012. Tumor necrosis factor alpha increases intestinal permeability in mice with fulminant hepatic failure. World J. Gastroenterol. 18, 5042-5050.
    • Liu, J., Jin, X., Liu, K.J., Liu, W., 2012. Matrix Metalloproteinase-2-Mediated Occludin Degradation and Caveolin-1-Mediated Claudin-5 Redistribution Contribute to Blood-Brain Barrier Damage in Early Ischemic Stroke Stage. J. Neurosci. 32, 3044-3057.
    • Massengale, J.L., Gasche, Y., Chan, P.H., 2002. Carbohydrate source influences gelatinase production by mouse astrocytes in vitro. Glia. 38, 240-245.
    • McColl, B.W., Rothwell, N.J., Allan, S.M., 2008. Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice. J. Neurosci. 28, 9451-9462.
    • Nagase, H., 1997. Activation mechanisms of matrix metalloproteinases. Biol. Chem. 378, 151- 160.
    • Nedergaard, M., Ransom, B., Goldman, S.A., 2003, New roles for astrocytes: redefining the functional architecture of the brain. Trends. Neurosci. 26, 523-530.
    • Pan, W., Ding, Y., Yu, Y., Ohtaki, H., Nakamachi, T., Kastin, A.J., 2006. Stroke upregulates TNF-alpha transport across the blood-brain barrier. Exp. Neurol. 198, 222-233.
    • Parks, W.C., Wilson, C.L., Lopez-Boado, Y.S., 2004. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617-629.
    • Rakkar, K., Srivastava, K., Bayraktutan, U., 2014. Attenuation of urokinase activity during experimental ischaemia protects the cerebral barrier from damage through regulation of matrix metalloproteinase-2 and NAD(P)H oxidase. Eur. J. Neurosci. 39, 2119-2128.
    • Reyes, R., Guo, M., Swann, K., Shetgeri, S.U., Sprague, S.M., Jimenez, D.F., Barone, C.M., Ding, Y., 2009. Role of tumor necrosis factor- α and matrix metalloproteinase-9 in bloodbrain barrier disruption after peripheral thermal injury in rats. J. Neurosurg. 110, 1218-1226.
    • Romanic, A.M., White, R.F., Arleth, A.J., Ohlstein, E.H., Barone, F.C., 1998. Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats: Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size. Stroke 29, 1020-1030.
    • Rosenberg, G.A., Estrada, E.Y., Dencoff, J.E., Hsu, C.Y., 1998. Matrix Metalloproteinases and TIMPs Are Associated With Blood-Brain Barrier Opening After Reperfusion in Rat Brain. Editorial Comment. Stroke 29, 2189-2195.
    • Sandoval, K.E., Witt, K.A., 2008. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol. Dis. 32, 200-219.
    • Scarabelli, T.M., Stephanou, A., Pasini, E., Comini, L., Raddino, R., Knight, R.A., Latchman, D.S., 2002. Different Signaling Pathways Induce Apoptosis in Endothelial Cells and Cardiac Myocytes During Ischemia/Reperfusion Injury. Circ. Res. 90, 745-748.
    • Sergeeva, M., Ubl, J.J., Reiser, G., 2000. Disruption of actin cytoskeleton in cultured rat astrocytes suppresses ATP- and bradykinin-induced [Ca(2+)](i) oscillations by reducing the coupling efficiency between Ca(2+) release, capacitative Ca(2+) entry, and store refilling. Neuroscience 97, 765-769.
    • Shao, B., Bayraktutan, U., 2013. Hyperglycaemia promotes cerebral barrier dysfunction through activation of protein kinase C-β. Diabetes, Obes. Metab. 15, 993-999.
    • Srivastava, K., Shao, B., Bayraktutan, U., 2013. PKC-beta exacerbates in vitro brain barrier damage in hyperglycemic settings via regulation of RhoA/Rho-kinase/MLC2 pathway. J. Cereb. Blood Flow Metab.33(12),1928-36.
    • Suh, S.W., Gum, E.T., Hamby, A.M., Chan, P.H., Swanson, R.A., 2007. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J. Clin. Invest. 117, 910-918.
    • Williams, R., Yao, H., Peng, F., Yang, Y., Bethel-Brown, C., Buch, S., 2010. Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia. Glia 58, 611-621.
    • Woodfin, A., Hu, D.-E., Sarker, M., Kurokawa, T., Fraser, P., 2011. Acute NADPH oxidase activation potentiates cerebrovascular permeability response to bradykinin in ischemiareperfusion. Free Radical Biol. Med. 50, 518-524.
    • Yang, G.-Y., Gong, C., Qin, Z., Liu, X.-H., Lorris Betz, A., 1999. Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice. Mol. Brain Res. 69, 135-143.
    • Yang, G.-Y., Gong, C., Qin, Z., Ye, W., Mao, Y., Bertz, A.L., 1998. Inhibition of TNFα attenuates infarct volume and ICAM-1 expression in ischemic mouse brain. NeuroReport. 9, 2131-2134.
    • Yang, Y., Estrada, E.Y., Thompson, J.F., Liu, W., Rosenberg, G.A., 2006. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is
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