Abstract
SummaryAimsHypoxia 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.MethodsMouse 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.ResultsHypoxia‐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.ConclusionPropofol could protect against hypoxia‐mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO‐1.
Highlights
The blood‐brain barrier (BBB) is a highly selective semipermeable border that separates the circulating blood from the brain and ex‐ tracellular fluid in the central nervous system (CNS)
We showed that hypoxia induced the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) (P < 0.05 vs normoxia, Figure 3A,B), which was at‐ tenuated by 100μΜ propofol pretreatment (P < 0.01 vs hy‐ poxia, Figure 3A,B)
We demonstrated in this study that propofol may inhibit hypoxia‐induced intracellular calcium accumulation and calm‐ odulin‐dependent protein kinase II (CAMKII) activation as well as zonula occludens‐1 (ZO‐1) phos‐ phorylation, implying the protective effect was mediated through calcium/CAMKII/zonula occludens (ZOs)‐1 pathway
Summary
The blood‐brain barrier (BBB) is a highly selective semipermeable border that separates the circulating blood from the brain and ex‐ tracellular fluid in the central nervous system (CNS) It restricts the diffusion of large or hydrophilic molecules, while allows the diffu‐ sion of hydrophobic and small polar molecules. Zonula occludens‐1 (ZO‐1) belongs to the family of ZOs and is proved to play an important role in keeping BBB integrity.[4] The func‐ tion of ZO‐1 may be modulated by its expression level and phos‐ phorylation status Multiple stimuli such as anesthesia and hypoxia may reduce the expression of ZO‐1, impairing the permeability of BBB in the in vitro and animal studies. Since hypoxia is known to be correlated with cal‐ cium overload and calcium signaling pathway, these factors were investigated in this study
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