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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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Related in: MedlinePlus

Proposed mechanisms of ruscogenin on BBB dysfunction after ischemic stroke. Upon hypoxia and ischemia, ROS is generated and MAPK activated; activated TXNIP activates the inactivated NLRP3 inflammasome, and triggers the expression of IL-1β and caspase-1, which contribute to the decreased tight junctions’ expression, stress fiber formation and changes in cell permeability. Ruscogenin ameliorates the ischemia-hypoxia-induced BBB disruption through upregulating the expression of tight junction proteins, and suppressing the expression of IL-1β and caspase-1, modulating the TXNIP/NLRP3 inflammasome activation and MAPK pathway.
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ijms-17-01418-f009: Proposed mechanisms of ruscogenin on BBB dysfunction after ischemic stroke. Upon hypoxia and ischemia, ROS is generated and MAPK activated; activated TXNIP activates the inactivated NLRP3 inflammasome, and triggers the expression of IL-1β and caspase-1, which contribute to the decreased tight junctions’ expression, stress fiber formation and changes in cell permeability. Ruscogenin ameliorates the ischemia-hypoxia-induced BBB disruption through upregulating the expression of tight junction proteins, and suppressing the expression of IL-1β and caspase-1, modulating the TXNIP/NLRP3 inflammasome activation and MAPK pathway.

Mentions: In conclusion, our present study further verifies the protective role of ruscogenin in MCAO/R-injured mice, and provides in vitro pharmacological evidence using OGD/R-injured bEnd.3 cells. In addition, our data also suggest that ruscogenin can protect against MCAO/R-induced BBB permeability and OGD/R-induced endothelial barrier function. Further studies found that the underlying mechanisms might be related to suppressing TXNIP/NLRP3 inflammasome activation (Figure 9). These findings might provide new insights and pharmacological evidence of its potential application for the prevention and treatment of ischemic stroke.


Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway
Proposed mechanisms of ruscogenin on BBB dysfunction after ischemic stroke. Upon hypoxia and ischemia, ROS is generated and MAPK activated; activated TXNIP activates the inactivated NLRP3 inflammasome, and triggers the expression of IL-1β and caspase-1, which contribute to the decreased tight junctions’ expression, stress fiber formation and changes in cell permeability. Ruscogenin ameliorates the ischemia-hypoxia-induced BBB disruption through upregulating the expression of tight junction proteins, and suppressing the expression of IL-1β and caspase-1, modulating the TXNIP/NLRP3 inflammasome activation and MAPK pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037697&req=5

ijms-17-01418-f009: Proposed mechanisms of ruscogenin on BBB dysfunction after ischemic stroke. Upon hypoxia and ischemia, ROS is generated and MAPK activated; activated TXNIP activates the inactivated NLRP3 inflammasome, and triggers the expression of IL-1β and caspase-1, which contribute to the decreased tight junctions’ expression, stress fiber formation and changes in cell permeability. Ruscogenin ameliorates the ischemia-hypoxia-induced BBB disruption through upregulating the expression of tight junction proteins, and suppressing the expression of IL-1β and caspase-1, modulating the TXNIP/NLRP3 inflammasome activation and MAPK pathway.
Mentions: In conclusion, our present study further verifies the protective role of ruscogenin in MCAO/R-injured mice, and provides in vitro pharmacological evidence using OGD/R-injured bEnd.3 cells. In addition, our data also suggest that ruscogenin can protect against MCAO/R-induced BBB permeability and OGD/R-induced endothelial barrier function. Further studies found that the underlying mechanisms might be related to suppressing TXNIP/NLRP3 inflammasome activation (Figure 9). These findings might provide new insights and pharmacological evidence of its potential application for the prevention and treatment of ischemic stroke.

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.

No MeSH data available.


Related in: MedlinePlus