Abstract
Yuzu and its main component, hesperidin (HSP), have several health benefits owing to their anti-inflammatory and antioxidant properties. We examined the effects of yuzu and HSP on blood–brain barrier (BBB) dysfunction during ischemia/hypoxia in an in vivo animal model and an in vitro BBB endothelial cell model, and also investigated the underlying mechanisms. In an in vitro BBB endothelial cell model, BBB permeability was determined by measurement of Evans blue extravasation in vivo and in vitro. The expression of tight junction proteins, such as claudin-5 and zonula occludens-1 (ZO-1), was detected by immunochemistry and western blotting, and the reactive oxygen species (ROS) level was measured by 2′7′-dichlorofluorescein diacetate intensity. Yuzu and HSP significantly ameliorated the increase in BBB permeability and the disruption of claudin-5 and ZO-1 in both in vivo and in vitro models. In bEnd.3 cells, yuzu and HSP were shown to inhibit the disruption of claudin-5 and ZO-1 during hypoxia, and the protective effects of yuzu and HSP on claudin-5 degradation seemed to be mediated by Forkhead box O 3a (FoxO3a) and matrix metalloproteinase (MMP)-3/9. In addition, well-known antioxidants, trolox and N-acetyl cysteine, significantly attenuated the BBB permeability increase, disruption of claudin-5 and ZO-1, and FoxO3a activation during hypoxia, suggesting that ROS are important mediators of BBB dysfunction during hypoxia. Collectively, these results indicate that yuzu and HSP protect the BBB against dysfunction via maintaining integrity of claudin-5 and ZO-1, and these effects of yuzu and HSP appear to be a facet of their antioxidant properties. Our findings may contribute to therapeutic strategies for BBB-associated neurodegenerative diseases.
Highlights
The blood–brain barrier (BBB) is a functional and structural barrier in the cerebrovascular endothelium that maintains brain homeostasis by regulating the influx of many compounds and pathogens from blood circulation into brain tissue [1]
These results suggest that the protective effects of yuzu and hSP on BBB permeability and tight junction (TJ) disruption may be associated with their antioxidant activities
We used siFoXO3a and observed that Forkhead box O 3a (FoxO3a) regulates claudin-5 degradation by inhibiting the process. we found no significant difference in zonula occludens-1 (ZO-1) redistribution between the control and siFoxO3a groups during hypoxia (Figure 5A)
Summary
The blood–brain barrier (BBB) is a functional and structural barrier in the cerebrovascular endothelium that maintains brain homeostasis by regulating the influx of many compounds and pathogens from blood circulation into brain tissue [1]. A normal BBB is characterized by endothelial cells with a few pinocytic vesicles, abundant mitochondria, and interendothelial tight junction (TJ) proteins. TJ proteins, such as zonula occludens-1 (ZO-1) and claudin-5 in the cerebrovascular endothelium, form the initial BBB between the systemic circulation and the central nervous system (CNS) [2]. The BBB acts as a gatekeeper for the CNS, effectively protecting the brain from detrimental substances [3]. The BBB is known to be disrupted under pathological conditions, such as neurodegenerative diseases. BBB breakdown has been reported to be a risk
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