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Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway

View Article: PubMed Central - PubMed

ABSTRACT

Ruscogenin, an important steroid sapogenin derived from Ophiopogon japonicus, has been shown to inhibit cerebral ischemic injury. However, its potential molecular action on blood-brain barrier (BBB) dysfunction after stroke remains unclear. This study aimed to investigate the effects of ruscogenin on BBB dysfunction and the underlying mechanisms in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen–glucose deprivation/reoxygenation (OGD/R)-injured mouse brain microvascular endothelial cells (bEnd.3). The results demonstrated that administration of ruscogenin (10 mg/kg) decreased the brain infarction and edema, improved neurological deficits, increased cerebral brain flow (CBF), ameliorated histopathological damage, reduced evans blue (EB) leakage and upregulated the expression of tight junctions (TJs) in MCAO/R-injured mice. Meanwhile, ruscogenin (0.1–10 µM) treatment increased cell viability and trans-endothelial electrical resistance (TEER) value, decreased sodium fluorescein leakage, and modulated the TJs expression in OGD/R-induced bEnd.3 cells. Moreover, ruscogenin also inhibited the expression of interleukin-1β (IL-1β) and caspase-1, and markedly suppressed the expression of Nucleotide-binding domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) and thiredoxin-interactive protein (TXNIP) in vivo and in vitro. Furthermore, ruscogenin decreased reactive oxygen species (ROS) generation and inhibited the mitogen-activated protein kinase (MAPK) pathway in OGD/R-induced bEnd.3 cells. Our findings provide some new insights into its potential application for the prevention and treatment of ischemic stroke.

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Effects of ruscogeinin on brain tissue injury in mice following MCAO/R. (A) The chemical structure of ruscogenin; (B) schematic diagram showing the experimental protocol. The experimental groups included the Sham group, Sham + RUS (ruscogenin) group, Model (MCAO/R) group and Model + RUS group. Ruscogenin was administrated intragastrically 1 h before occlusion, and the mice were reperfused after MCAO 1 h and sacrificed after a further 24 h, respectively; (C,D) representative of TTC-stained brain sections and quantitative analysis of infarct volume in different groups; (E,F) quantitation of brain water contents and neurological deficits scores in different groups. ND means “not detected”. NS means “not significant”. The data (n = 6) are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
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ijms-17-01418-f001: Effects of ruscogeinin on brain tissue injury in mice following MCAO/R. (A) The chemical structure of ruscogenin; (B) schematic diagram showing the experimental protocol. The experimental groups included the Sham group, Sham + RUS (ruscogenin) group, Model (MCAO/R) group and Model + RUS group. Ruscogenin was administrated intragastrically 1 h before occlusion, and the mice were reperfused after MCAO 1 h and sacrificed after a further 24 h, respectively; (C,D) representative of TTC-stained brain sections and quantitative analysis of infarct volume in different groups; (E,F) quantitation of brain water contents and neurological deficits scores in different groups. ND means “not detected”. NS means “not significant”. The data (n = 6) are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.

Mentions: Ruscogenin (for which the chemical structure shown in Figure 1A) is a major bioactive steroid sapogenin that is found in the roots of Ophiopogon japonicus (Thumb.) Ker-Gawl., and it has been widely used for the treatment of chronic inflammatory and cardiovascular diseases for many years [19,20]. Pharmacological studies have demonstrated that ruscogenin exerts its beneficial effects on mouse neutrophil activation and pulmonary arterial hypertension, mainly due to its anti-inflammatory and anti-thrombotic activities [21,22]. Furthermore, ruscogenin has been confirmed to reduce cerebral ischemic injury via the nuclear factor-κB (NF-κB)-mediated inflammatory pathway in mice [23]. However, the effects and potential mechanisms of ruscogenin on the BBB dysfunction or inflammasome activation remain to be explored.


Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway
Effects of ruscogeinin on brain tissue injury in mice following MCAO/R. (A) The chemical structure of ruscogenin; (B) schematic diagram showing the experimental protocol. The experimental groups included the Sham group, Sham + RUS (ruscogenin) group, Model (MCAO/R) group and Model + RUS group. Ruscogenin was administrated intragastrically 1 h before occlusion, and the mice were reperfused after MCAO 1 h and sacrificed after a further 24 h, respectively; (C,D) representative of TTC-stained brain sections and quantitative analysis of infarct volume in different groups; (E,F) quantitation of brain water contents and neurological deficits scores in different groups. ND means “not detected”. NS means “not significant”. The data (n = 6) are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037697&req=5

ijms-17-01418-f001: Effects of ruscogeinin on brain tissue injury in mice following MCAO/R. (A) The chemical structure of ruscogenin; (B) schematic diagram showing the experimental protocol. The experimental groups included the Sham group, Sham + RUS (ruscogenin) group, Model (MCAO/R) group and Model + RUS group. Ruscogenin was administrated intragastrically 1 h before occlusion, and the mice were reperfused after MCAO 1 h and sacrificed after a further 24 h, respectively; (C,D) representative of TTC-stained brain sections and quantitative analysis of infarct volume in different groups; (E,F) quantitation of brain water contents and neurological deficits scores in different groups. ND means “not detected”. NS means “not significant”. The data (n = 6) are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
Mentions: Ruscogenin (for which the chemical structure shown in Figure 1A) is a major bioactive steroid sapogenin that is found in the roots of Ophiopogon japonicus (Thumb.) Ker-Gawl., and it has been widely used for the treatment of chronic inflammatory and cardiovascular diseases for many years [19,20]. Pharmacological studies have demonstrated that ruscogenin exerts its beneficial effects on mouse neutrophil activation and pulmonary arterial hypertension, mainly due to its anti-inflammatory and anti-thrombotic activities [21,22]. Furthermore, ruscogenin has been confirmed to reduce cerebral ischemic injury via the nuclear factor-κB (NF-κB)-mediated inflammatory pathway in mice [23]. However, the effects and potential mechanisms of ruscogenin on the BBB dysfunction or inflammasome activation remain to be explored.

View Article: PubMed Central - PubMed

ABSTRACT

Ruscogenin, an important steroid sapogenin derived from Ophiopogon japonicus, has been shown to inhibit cerebral ischemic injury. However, its potential molecular action on blood-brain barrier (BBB) dysfunction after stroke remains unclear. This study aimed to investigate the effects of ruscogenin on BBB dysfunction and the underlying mechanisms in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen&ndash;glucose deprivation/reoxygenation (OGD/R)-injured mouse brain microvascular endothelial cells (bEnd.3). The results demonstrated that administration of ruscogenin (10 mg/kg) decreased the brain infarction and edema, improved neurological deficits, increased cerebral brain flow (CBF), ameliorated histopathological damage, reduced evans blue (EB) leakage and upregulated the expression of tight junctions (TJs) in MCAO/R-injured mice. Meanwhile, ruscogenin (0.1&ndash;10 &micro;M) treatment increased cell viability and trans-endothelial electrical resistance (TEER) value, decreased sodium fluorescein leakage, and modulated the TJs expression in OGD/R-induced bEnd.3 cells. Moreover, ruscogenin also inhibited the expression of interleukin-1&beta; (IL-1&beta;) and caspase-1, and markedly suppressed the expression of Nucleotide-binding domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) and thiredoxin-interactive protein (TXNIP) in vivo and in vitro. Furthermore, ruscogenin decreased reactive oxygen species (ROS) generation and inhibited the mitogen-activated protein kinase (MAPK) pathway in OGD/R-induced bEnd.3 cells. Our findings provide some new insights into its potential application for the prevention and treatment of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus