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

Abstract

Summary 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 Ca 2+ /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.

Propofol attenuated TNF-α-modulated occludin expression by inhibiting Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway in hCMEC/D3 cells

“…In addition, the supplementary data showed that propofol had no effect on TNF-α-modulated ZO-1 expression. Although it has been reported that propofol attenuated hypoxia-modulated ZO-1 expression in mouse brain microvascular endothelial cells [27,32]. We reasoned that hypoxia and inflammation may reduce ZO-1 expression through different intracellular signaling pathway, and that propofol may have different effect on these pathways.…”

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

“…41 Previous studies of BBB permeability in CSVD have focused on tight junction proteins, such as zonula occludens-1 (ZO-1), occludin, and claudin-5. 42,43 The decreased expression of claudin-5, the key tight junction protein of the BBB, has been reported in a CSVD model. 38 In addition, growing evidence has indicated that limited caveolae-mediated transcytosis maintains BBB integrity in the CNS, 44 and BBB disruption due to increased vesicle transport has been confirmed in many models.…”

“…The impairment of the BBB predicts cognitive impairment at one year . Previous studies of BBB permeability in CSVD have focused on tight junction proteins, such as zonula occludens‐1 (ZO‐1), occludin, and claudin‐5 . The decreased expression of claudin‐5, the key tight junction protein of the BBB, has been reported in a CSVD model .…”

Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells

“…In addition, the supplementary data showed that propofol had no effect on TNF-αmodulated ZO-1 expression. Although it has been reported that propofol could attenuate hypoxiamodulated ZO-1 expression in mouse brain microvascular endothelial cells [ 27,32]. We reasoned that hypoxia and inflammation may reduce ZO-1 expression through different intracellular signaling pathway, and that propofol may have different effect on these pathways.…”