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CNS Neurosci Ther. 2019 Jun;25(6):704-713. doi: 10.1111/cns.13101. Epub 2019 Jan 24.

Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1.

Chen W1,2, Ju XZ2,3, Lu Y1,2, Ding XW1,2, Miao CH1,2, Chen JW1,2.

Author information

1
Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
2
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
3
Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Abstract

AIMS:

Hypoxia may damage blood-brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia-induced impairment of BBB integrity.

METHODS:

Mouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens-1 (ZO-1) expression and phosphorylation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca2+ /calmodulin-dependent protein kinase II (CAMKII) activation were measured.

RESULTS:

Hypoxia-impaired BBB integrity, which was protected by propofol. Hypoxia-reduced ZO-1 expression, while induced ZO-1 phosphorylation. These effects were attenuated by propofol. The expression of HIF-1α and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia-mediated suppression of ZO-1 and impaired BBB integrity was reversed by HIF-α inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia-induced phosphorylation of ZO-1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor.

CONCLUSION:

Propofol could protect against hypoxia-mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO-1.

KEYWORDS:

blood-brain barrier; hypoxia; mouse brain microvascular endothelial cells; propofol; zonula occludens-1

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