The Protective Effects of Juglanin in Cerebral Ischemia Reduce Blood-Brain Barrier Permeability via Inhibition of VEGF/VEGFR2 Signaling.

Ischemic brain injury due to stroke or other pathologies is a major contributor to disability and mortality worldwide. Upon the occurrence of stroke, neuronal cells undergo apoptosis due to the deprivation of oxygen and nutrients and failure of the blood-brain barrier (BBB). In the moments immediately following a stroke, widespread perfusion resulting from hyperpermeability is accompanied by an acute inflammatory response, which induces neovascularization and often permanent neurological injury. Vascular endothelial growth factor (VEGF) and its receptor VEGF receptor 2 (VEGFR2) have been targeted to suppress cerebral ischemia. Recently, natural products including flavonoids, such as juglanin, have been receiving increasing attention for their impressive physiological effects. Twenty mg/kg body weight juglanin was administrated for 3 weeks before inducing middle cerebral artery occlusion (MCAO) in mice. The animal brain infarction volume, neurological deficit score, blood-brain barrier permeability, and the expression of tight junction proteins were evaluated. Endothelial permeability and tight junction protein expression were also assessed in brain microvascular endothelial cells (HMBVECs) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). Juglanin significantly reduced occlusion-induced infarct volume and improved neurological score by suppressing BBB hyperpermeability. Juglanin inhibited both the mRNA and protein expression of VEGF and VEGFR2 and restored the normal expression of occludin and zonula occludens-1 (ZO-1), two important tight junction proteins, in MCAO mice. Meanwhile, the results of in vitro experiments show that the protective effects of juglanin against increased BBB permeability and reduced tight junction functionality are dependent on the VEGF/VEGFR2 signaling pathway, as evidenced by the capacity of exogenous VEGF-A to abolish the effects of juglanin. Our findings indicate a potent ability of juglanin to prevent neuronal injury resulting from cerebral ischemia by modulating the VEGF/VEGFR2 signaling pathway. Further research will help elucidate the exact mechanisms behind the protective effects of juglanin.

Liu J ，Chen L ，Zhang X ，Pan L ，Jiang L ... -  《Drug Design Development and Therapy》

Cepharanthine maintains integrity of the blood-brain barrier (BBB) in stroke via the VEGF/VEGFR2/ZO-1 signaling pathway.

Yang Y ，Li C ，Yang S ，Zhang Z ，Bai X ，Tang H ，Huang J ... -  《Aging-US》

Hypertonic saline alleviates experimentally induced cerebral oedema through suppression of vascular endothelial growth factor and its receptor VEGFR2 expression in astrocytes.

Huang L ，Cao W ，Deng Y ，Zhu G ，Han Y ，Zeng H ... -  《BMC NEUROSCIENCE》

Hypertonic saline downregulates endothelial cell-derived VEGF expression and reduces blood-brain barrier permeability induced by cerebral ischaemia via the VEGFR2/eNOS pathway.

Wang Q ，Deng Y ，Huang L ，Zeng W ，Chen S ，Lv B ，Jiang W ，Han Y ，Ding H ，Wen M ，Zeng H ... -  《-》

Vascular endothelial growth factor aggravates cerebral ischemia and reperfusion-induced blood-brain-barrier disruption through regulating LOC102640519/HOXC13/ZO-1 signaling.

Vascular endothelial growth factor (VEGF) has been recognized to be a potential pharmaceutical target for treating ischemic stroke, but its severe side effects hinder its widely application. Here, the present study was designed to investigate the effects of VEGF on blood-brain-barrier (BBB) disruption and the underlying mechanisms. A mouse model of middle cerebral artery occlusion (MCAO) was constructed and treated with or without VEGF. Meanwhile, mice brain microvascular endothelial cells in co-culture with astrocytes were subjected to 1, 2 and 4 h oxygen-glucose deprivation followed by 24 h of reperfusion (OGD/R) in the absence or presence of VEGF. The mRNA and protein expression were assessed by real-time PCR and Western blotting. Fluorescence in situ hybridization (FISH) was utilized to validate LOC102640519 expression in OGD/R cell models. Chromatin Immunoprecipitation (ChIP) assay was used to confirm the regulatory mechanism of LOC102640519 to HOXC13. Interactions between HOXC13 and ZO-1 were measured by a luciferase reporter assay and RNA pull down assay. Our results showed that administration of VEGF significantly aggravated BBB by upregulating LOC102640519 and HOXC13 expression in vitro and vitro model of cerebral ischemia. Furthermore, LOC102640519 positively regulated the expression of HOXC13, thus negatively regulated the expression of ZO-1, Occludin and Claudin-5 in OGD/R model in the absence or presence of VEGF. VEGF aggravated BBB disruption after cerebral I/R-induced injury probably by increasing LOC102640519 and HOXC13 through inhibition of ZO-1, Occludin and Claudin-5.

Wu L ，Ye Z ，Pan Y ，Li X ，Fu X ，Zhang B ，Li Y ，Lin W ，Li X ，Gao Q ... -  《-》