title: Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway.
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.
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. caoguosheng2006@163.com.
authors: Guosheng
authors: G
authors: Cao
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. nancyjiangnan@163.com.
authors: Nan
authors: N
authors: Jiang
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. huyangzi2014@163.com.
authors: Yang
authors: Y
authors: Hu
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. cpuzhang27@163.com.
authors: Yuanyuan
authors: Y
authors: Zhang
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. wgyhefei@163.com.
authors: Guangyun
authors: G
authors: Wang
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. yinmingzhu2008@126.com.
authors: Mingzhu
authors: M
authors: Yin
authors: Cellular and Molecular Biology Center, China Pharmaceutical University, Nanjing 211198, China. maxiaonan512@126.com.
authors: Xiaonan
authors: X
authors: Ma
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. yuefei_86@126.com.
authors: Kecheng
authors: K
authors: Zhou
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. yaoyuelingxing@163.com.
authors: Jin
authors: J
authors: Qi
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. boyangyu59@163.com.
authors: Boyang
authors: B
authors: Yu
authors: Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China. junpingkou@cpu.edu.cn.
authors: Junping
authors: J
authors: Kou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D031441:Ophiopogon / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013150:Spirostans / Q000494:pharmacology* / Q000627:therapeutic use; D013879:Thioredoxins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D013150:Spirostans; C445672:Txnip protein, mouse; D013879:Thioredoxins; C012541:ruscogenin; D020170:Caspase 1
keywords: MAPK; blood-brain barrier; inflammasome; ischemic stroke; ruscogenin