Yuzu and Hesperidin Ameliorate Blood-Brain Barrier Disruption during Hypoxia via Antioxidant Activity

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.

Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury

“…After SCI, mitochondrial ROS increase has been detected within 24 h [ 23 ], and inhibition of ROS production might protect injured spinal cord from mitochondrial oxidative stress and neuronal apoptosis [ 24 ]. There is evidence that ROS level of vascular endothelial cells is upregulated in cerebrovascular disease, and it subsequently impairs the integrity of BBB [ 25 ]. Therefore, it is necessary to maintain mitochondrial homeostasis in vascular endothelial cells after SCI.…”

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

“…Flavanones are a class of flavonoids that include pinocembrin and hesperidin. They can attenuate BBB dysfunction under oxidative stress [ 194 , 195 ].…”

“…In bEnd3 cells, hesperidin exerted antioxidative effects by scavenging ROS and inhibiting FoxO3a translocation, which was reported to regulate the expression of genes related to apoptosis and oxidative stress. Therefore, ROS can contribute to the regulation of BBB integrity as an upstream signaling pathway for FoxO3a/MMP3 and MMP9-mediated degradation of claudin-5 and redistribution of ZO-1 [ 195 ].…”

Auraptene Enhances Junction Assembly in Cerebrovascular Endothelial Cells by Promoting Resilience to Mitochondrial Stress through Activation of Antioxidant Enzymes and mtUPR

“…ROS have been found to increase the permeability of the BBB by altering tight junctions, suggesting that therapeutic targeting of the regulation of antioxidant activity can preserve the integrity of the BBB [ 37 , 38 ]. The relationship between antioxidant enzymes and junction expression has also been observed in intestinal epithelial cells, which have barrier functions similar to that of the BBB.…”