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

• Published in: International journal of molecular sciences Vol. 17; no. 9; p. 1418
• Main Authors: Cao, Guosheng, Jiang, Nan, Hu, Yang, Zhang, Yuanyuan, Wang, Guangyun, Yin, Mingzhu, Ma, Xiaonan, Zhou, Kecheng, Qi, Jin, Yu, Boyang, Kou, Junping
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 01.09.2016; MDPI AG
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antioxidants - pharmacology; Antioxidants - therapeutic use; blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Carrier Proteins - metabolism; Caspase 1 - genetics; Caspase 1 - metabolism; Cell Hypoxia; Cell Line; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; inflammasome; Inflammasomes - drug effects; Inflammasomes - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; ischemic stroke; Male; MAP Kinase Signaling System; MAPK; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Ophiopogon - chemistry; Reactive Oxygen Species - metabolism; ruscogenin; Spirostans - pharmacology; Spirostans - therapeutic use; Thioredoxins - metabolism; Tight Junctions - drug effects; Tight Junctions - metabolism; blood-brain barrier; ruscogenin; MAPK; inflammasome; ischemic stroke
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms17091418

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.