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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.

No MeSH data available.


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Effects of ruscogenin on histopathological changes and CBF in mice following MCAO/R. (A) Hematoxylin-and-eosin-stained slides of the brain sections of mouse in different groups; (B,C) representative images and quantitative analysis of cerebral blood flow of ipsilateral cortex in different groups. The magnitude of CBF is represented by different colors, with blue to red denoting low to high respectively (n = 6). NS means “not significant”. The data are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
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ijms-17-01418-f002: Effects of ruscogenin on histopathological changes and CBF in mice following MCAO/R. (A) Hematoxylin-and-eosin-stained slides of the brain sections of mouse in different groups; (B,C) representative images and quantitative analysis of cerebral blood flow of ipsilateral cortex in different groups. The magnitude of CBF is represented by different colors, with blue to red denoting low to high respectively (n = 6). NS means “not significant”. The data are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.

Mentions: As Figure 2 shows, the hematoxylin and eosin (H & E) staining results demonstrated that the model group experienced neuronal loss and the presence of numerous vacuolated spaces; pretreatment with ruscogenin (10 mg/kg) could ameliorate histopathological damage by decreasing the cell loss compared with the model group (Figure 2A). Meanwhile, the quantification of cerebral blood flow (CBF) result showed that the administration of ruscogenin resulted in a significant increase in CBF compared with model group at 24 h reperfusion (Figure 2B,C). No obvious change was observed between Sham and Sham + RUS in the above experiments.


Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway
Effects of ruscogenin on histopathological changes and CBF in mice following MCAO/R. (A) Hematoxylin-and-eosin-stained slides of the brain sections of mouse in different groups; (B,C) representative images and quantitative analysis of cerebral blood flow of ipsilateral cortex in different groups. The magnitude of CBF is represented by different colors, with blue to red denoting low to high respectively (n = 6). NS means “not significant”. The data are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
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Related In: Results  -  Collection

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ijms-17-01418-f002: Effects of ruscogenin on histopathological changes and CBF in mice following MCAO/R. (A) Hematoxylin-and-eosin-stained slides of the brain sections of mouse in different groups; (B,C) representative images and quantitative analysis of cerebral blood flow of ipsilateral cortex in different groups. The magnitude of CBF is represented by different colors, with blue to red denoting low to high respectively (n = 6). NS means “not significant”. The data are expressed as means ± SD. ##p < 0.01 vs. Sham, ** p < 0.01 vs. Model.
Mentions: As Figure 2 shows, the hematoxylin and eosin (H & E) staining results demonstrated that the model group experienced neuronal loss and the presence of numerous vacuolated spaces; pretreatment with ruscogenin (10 mg/kg) could ameliorate histopathological damage by decreasing the cell loss compared with the model group (Figure 2A). Meanwhile, the quantification of cerebral blood flow (CBF) result showed that the administration of ruscogenin resulted in a significant increase in CBF compared with model group at 24 h reperfusion (Figure 2B,C). No obvious change was observed between Sham and Sham + RUS in the above experiments.

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