Panaxadiol Attenuates Brain Damage by Inhibiting Ferroptosis in a Rat Model of Cerebral Hemorrhage

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL
Min Zhao, Yu Wang, Jing Li, Quan Wen, Yue Liu, Yanan Zhao
{"title":"Panaxadiol Attenuates Brain Damage by Inhibiting Ferroptosis in a Rat Model of Cerebral Hemorrhage","authors":"Min Zhao,&nbsp;Yu Wang,&nbsp;Jing Li,&nbsp;Quan Wen,&nbsp;Yue Liu,&nbsp;Yanan Zhao","doi":"10.1002/ddr.70079","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhage stroke, with a high disability, morbidity and mortality rate globally. Panaxadiol (PD), a triterpenoid sapogenin monomer, is isolated from the roots of ginseng, which has shown a variety of biological properties, such as anti-inflammation, anti-cancer, and neuroprotection. However, its effect and mechanism on ICH were still unknown. Thirty-six rats were randomly divided into six group (<i>n</i> = 6), namely, sham, ICH, ICH + 5 mg/kg PD, ICH + 10 mg/kg PD, ICH + 20 mg/kg PD, and ICH + 10 mg/kg PD + 50 mg/kg vismodegib. Rats were treated with type IV collagenase to induce an in vivo model of ICH, and then intraperitoneally injected with PD (5, 10 and 20 mg/kg) and 50 mg/kg vismodegib (an inhibitor of hedgehog signal). The effect and potential mechanism of PD on ICH were explored by behavioral test, brain water content measurement, Evans blue detection, hematoxylin-eosin (HE) staining, iron level examination, Prussian blue staining, western blot and immunohistochemistry, respectively. An increase in the mNSS (13.17 ± 1.17), and a decrease in the rotarod latency (40.67 ± 9.31), modified Garcia score (9.83 ± 1.47), forelimb use times (3.33 ± 0.82), left forepaw placements (29.90 ± 4.38) and left turns (17.34 ± 3.55) in ICH rats were reversed with the PD treatment (6.83 ± 0.75, 113.5 ± 11.95, 17.50 ± 1.87, 8.17 ± 0.98, 63.56 ± 9.84, and 42.13 ± 4.52 respectively). PD treatment reduced the brain water content (73.13 ± 3.16 vs. 86.82 ± 4.74), the level of Evans blue (2.14 ± 0.25 vs. 4.03 ± 0.20) and cerebral hemorrhage in ICH rats. Also, PD injection decreased the iron level (0.06 ± 0.005 vs. 0.17 ± 0.02) and the expression of ACSL4 (0.56 ± 0.07 vs. 1.23 ± 0.16), with the increased expression of GPX4 (1.14 ± 0.08 vs. 0.21 ± 0.03) in ICH rats. Mechanically, PD treatment restored the decreased expression of SHH (0.96 ± 0.13 vs. 0.20 ± 0.03), GLI1 (0.89 ± 0.13 vs. 0.06 ± 0.007) and PTCH (0.75 ± 0.05 vs. 0.10 ± 0.01) in ICH rats. Inhibition of SHH signaling by vismodegib reversed the ameliorative effect of PD on ICH rats. PD improved brain damage by suppressing ferroptosis via the activation of the SHH/GLI signaling pathway, which could lay a theoretical foundation for the treatment of ICH.</p>\n </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70079","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhage stroke, with a high disability, morbidity and mortality rate globally. Panaxadiol (PD), a triterpenoid sapogenin monomer, is isolated from the roots of ginseng, which has shown a variety of biological properties, such as anti-inflammation, anti-cancer, and neuroprotection. However, its effect and mechanism on ICH were still unknown. Thirty-six rats were randomly divided into six group (n = 6), namely, sham, ICH, ICH + 5 mg/kg PD, ICH + 10 mg/kg PD, ICH + 20 mg/kg PD, and ICH + 10 mg/kg PD + 50 mg/kg vismodegib. Rats were treated with type IV collagenase to induce an in vivo model of ICH, and then intraperitoneally injected with PD (5, 10 and 20 mg/kg) and 50 mg/kg vismodegib (an inhibitor of hedgehog signal). The effect and potential mechanism of PD on ICH were explored by behavioral test, brain water content measurement, Evans blue detection, hematoxylin-eosin (HE) staining, iron level examination, Prussian blue staining, western blot and immunohistochemistry, respectively. An increase in the mNSS (13.17 ± 1.17), and a decrease in the rotarod latency (40.67 ± 9.31), modified Garcia score (9.83 ± 1.47), forelimb use times (3.33 ± 0.82), left forepaw placements (29.90 ± 4.38) and left turns (17.34 ± 3.55) in ICH rats were reversed with the PD treatment (6.83 ± 0.75, 113.5 ± 11.95, 17.50 ± 1.87, 8.17 ± 0.98, 63.56 ± 9.84, and 42.13 ± 4.52 respectively). PD treatment reduced the brain water content (73.13 ± 3.16 vs. 86.82 ± 4.74), the level of Evans blue (2.14 ± 0.25 vs. 4.03 ± 0.20) and cerebral hemorrhage in ICH rats. Also, PD injection decreased the iron level (0.06 ± 0.005 vs. 0.17 ± 0.02) and the expression of ACSL4 (0.56 ± 0.07 vs. 1.23 ± 0.16), with the increased expression of GPX4 (1.14 ± 0.08 vs. 0.21 ± 0.03) in ICH rats. Mechanically, PD treatment restored the decreased expression of SHH (0.96 ± 0.13 vs. 0.20 ± 0.03), GLI1 (0.89 ± 0.13 vs. 0.06 ± 0.007) and PTCH (0.75 ± 0.05 vs. 0.10 ± 0.01) in ICH rats. Inhibition of SHH signaling by vismodegib reversed the ameliorative effect of PD on ICH rats. PD improved brain damage by suppressing ferroptosis via the activation of the SHH/GLI signaling pathway, which could lay a theoretical foundation for the treatment of ICH.

Panaxadiol通过抑制大鼠脑出血模型中的铁下垂来减轻脑损伤。
脑出血(ICH)是出血性卒中最常见的亚型,在全球范围内具有高致残率、发病率和死亡率。Panaxadiol (PD)是一种从人参根中分离得到的三萜皂苷元单体,具有抗炎、抗癌、神经保护等多种生物学特性。但其对脑出血的作用及机制尚不清楚。36只大鼠随机分为6组(n = 6),分别为假手术、ICH、ICH + 5 mg/kg PD、ICH + 10 mg/kg PD、ICH + 20 mg/kg PD、ICH + 10 mg/kg PD + 50 mg/kg维莫替吉。采用IV型胶原酶诱导大鼠脑出血模型,然后腹腔注射PD(5、10、20 mg/kg)和vismodegib(一种刺猬信号抑制剂)50 mg/kg。分别通过行为学实验、脑含水量测定、Evans蓝检测、苏木精-伊红(HE)染色、铁水平检测、普鲁士蓝染色、western blot和免疫组化等方法探讨PD对脑出血大鼠的影响及其可能机制。PD治疗后脑出血大鼠的mNSS增加(13.17±1.17),轮轮潜伏期减少(40.67±9.31),改良Garcia评分减少(9.83±1.47),前肢使用次数减少(3.33±0.82),左前爪放置(29.90±4.38),左转弯(17.34±3.55),分别为6.83±0.75,113.5±11.95,17.50±1.87,8.17±0.98,63.56±9.84,42.13±4.52)。PD治疗降低脑出血大鼠脑含水量(73.13±3.16比86.82±4.74)、埃文斯蓝水平(2.14±0.25比4.03±0.20)及脑出血。PD注射降低了ICH大鼠的铁水平(0.06±0.005比0.17±0.02),ACSL4表达(0.56±0.07比1.23±0.16),GPX4表达(1.14±0.08比0.21±0.03)。机械上,PD治疗恢复了ICH大鼠SHH(0.96±0.13比0.20±0.03)、GLI1(0.89±0.13比0.06±0.007)和PTCH(0.75±0.05比0.10±0.01)的表达。vismodegib对SHH信号的抑制逆转了PD对ICH大鼠的改善作用。PD通过激活SHH/GLI信号通路抑制铁下垂,改善脑损伤,为脑出血的治疗奠定理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信