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NADPH oxidase mediates TNF-α-evoked in vitro brain barrier dysfunction: roles of apoptosis and time

Abdullah, Zuraidah; Bayraktutan, Ulvi

Authors

Zuraidah Abdullah

Ulvi Bayraktutan



Abstract

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.

Journal Article Type Article
Publication Date Jul 1, 2014
Journal Molecular and Cellular Neuroscience
Print ISSN 1044-7431
Electronic ISSN 1044-7431
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 61
APA6 Citation Abdullah, Z., & Bayraktutan, U. (2014). NADPH oxidase mediates TNF-α-evoked in vitro brain barrier dysfunction: roles of apoptosis and time. Molecular and Cellular Neuroscience, 61, doi:10.1016/j.mcn.2014.06.002
DOI https://doi.org/10.1016/j.mcn.2014.06.002
Keywords TNF-α; Blood–brain barrier; NADPH oxidase; MMP; Cytoskeleton
Publisher URL http://www.sciencedirect.com/science/article/pii/S1044743114000633
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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