首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1322211034765578567, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322210968248107603, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202501047, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1736956800000, receivedDateStr=2025-01-16, revisedDate=1739721600000, revisedDateStr=2025-02-17, acceptedDate=null, acceptedDateStr=null, onlineDate=1793169276180, onlineDateStr=2026-10-28, pubDate=1747238400000, pubDateStr=2025-05-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793169276180, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793169276180, creator=13701087609, updateTime=1793169276180, updator=13701087609, issue=Issue{id=1322210968248107603, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='9', pageStart='893', pageEnd='1028', issueExtLink='null', onlineDate='null', pubDate='1747238400000', pubDateStr='2025-05-15', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793169260321, creator='13701087609', updateTime=1793325292291, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322865413818536367, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322210968248107603, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322865413818536368, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322210968248107603, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=922, endPage=934, ext={EN=ArticleExt(id=1322211034958516552, articleId=1322211034765578567, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Effects and underlying mechanisms of novel phenothiazine derivative DA414 in rats with intracerebral hemorrhage, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective‍

To explore the efficacy and action mechanism of a novel phenothiazine derivative, DA414, in rats with intracerebral hemorrhage (ICH).

Methods‍

Male Sprague-Dawley (SD) rats (aged 8~10 weeks, weighing 250~300 g) were randomly divided into sham operation, model, and low and high dose DA414 groups [5 and 10 mg/(kg·d)], with20 animals per group. The size and extent of injury in the ICH area were measured by magnetic resonance imaging (MRI) and histopathological slices. Neurological function was evaluated with a behavioral grading system. Western blotting was used to detect the expression of ferroptosis-related factor, glutathione peroxidase 4 (GPX4). Multiplex immunohistochemistry was employed to quantitatively evaluate microglial activation in perihematomal tissue. RT-qPCR was applied to measure the mRNA expression levels of NLRP3 inflammasome components (NLRP3, Caspase-1, IL-1β), pro-inflammatory (IL-18, TLR4, IL-6, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10). The integrity of the blood-brain barrier (BBB) was assessed by Evans blue staining, and the biosafety of DA414 for the liver, kidneys and heart was assessed by HE staining and clinical biochemical tests.

Results‍

DA414 significantly promoted the absorption of hematoma, reduced neuronal injury, and improved neurological function scores. DA414 significantly up-regulated the ferroptosis regulatory factor GPX4 (P<0.01), and also significantly inhibited the activation of microglia after ICH (P<0.001). RT-qPCR indicated that DA414 treatment resulted in down-regulation of mRNA expression in the inflammasome pathway (NLRP3, Caspase-1, IL-1β, all P<0.01) and pro-inflammatory cytokines (TLR4, IL-6, both P<0.05; IL-18, TNF-α, both P<0.01) and up-regulation of anti-inflammatory cytokines (IL-4, IL-10, both P<0.05), suggesting that DA414 exerts its neuroprotective effect probably by regulating ferroptosis and inflammation. Safety assessment revealed that DA414 had no significant effect on BBB integrity or damage to the liver, kidneys, and heart in rats.

Conclusion‍

DA414 exerts significant neuroprotective effects in ICH model by targeted inhibition for ferroptosis and modulating inflammatory response. Our study provides an experimental foundation for ICH treatment.

, authors=Yufan MA, Bingqiao WANG, Sen LIN, Qingwu YANG, authorsList=Yufan MA, Bingqiao WANG, Sen LIN, Qingwu YANG, authorCompany=null, correspAuthors=Qingwu YANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322211038133604695, articleId=1322211034765578567, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=新型吩噻嗪衍生物DA414在大鼠脑出血中的作用及机制研究, columnId=1322185528879993170, journalTitle=陆军军医大学学报, columnName=基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

探讨新型吩噻嗪衍生物DA414对脑出血（intracerebral hemorrhage，ICH）大鼠的疗效及作用机制。

方法

雄性SD大鼠（8~10周龄，体质量250~300 g）按随机数字表法分为假手术组、模型组、5 mg/（kg·d） DA414组和10 mg/（kg·d）DA414组，每组20只。采用磁共振成像（magnetic resonance imaging， MRI）及组织切片定量分析ICH区域的大小及损伤程度；神经功能通过行为学进行评估；Western blot探讨DA414对铁死亡调节因子谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4） 的表达影响；多重荧光免疫组化对血肿周围组织小胶质细胞活化状态定量分析；RT-qPCR检测炎症小体通路（NLRP3、Caspase-1、IL-1β）及促炎（IL-18、TLR4、IL-6、TNF-α）和抗炎（IL-4、IL-10）细胞因子的mRNA表达水平。通过伊文思蓝染色评估血脑屏障（blood-brain barrier，BBB）的完整性，HE染色和临床生化检验评估DA414对肝脏、肾脏和心脏的安全性。

结果

DA414显著促进了ICH后血肿的吸收，减少神经损伤，并显著改善神经功能评分。与模型组相比，DA414处理能够显著上调铁死亡调节因子GPX4的水平（P<0.01）；且显著抑制了ICH后小胶质活化（P<0.001）；RT-qPCR进一步证实其下调炎症小体通路NLRP3（P<0.01）、Caspase-1（P<0.01）、IL-1β（P<0.01）及促炎因子IL-18（P<0.01）、TLR4（P<0.05）、IL-6（P<0.05）、TNF-α（P<0.01），同时上调抗炎细胞因子IL-4、IL-10 mRNA表达（P<0.05），提示其神经保护作用可能通过调节铁死亡及炎症双重机制实现。安全性评估进一步表明DA414干预对大鼠BBB无明显影响，且其对肝脏、肾脏、心脏也无明显损伤。

结论

DA414通过靶向抑制铁死亡并调节炎症反应，在ICH模型中表现出显著神经保护效应，为ICH治疗提供实验基础。

, authors=马渝凡, 王柄乔, 林森, 杨清武, authorsList=马渝凡, 王柄乔, 林森, 杨清武, authorCompany=null, correspAuthors=杨清武, authorNote=

同等贡献者

MA Yufan and WANG Bingqiao contributed equally to the article.

, correspAuthorsNote=
杨清武，E-mail：
YANG Qingwu，E-mail：
, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=VDyqZh3Qias4Ub5eCy8otw==, magXml=4usNGbGPV42Aql2ei6MWUA==, pdfUrl=null, pdf=OWVtxbAupwuTe4/pcRCt8w==, pdfFileSize=4159631, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=8bvm11hRFNjFWQ1b9ezXbg==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=xDtax56wItYPe6JYAr1VnA==, mapNumber=null, fund=null)}, authors=[Author(id=1322211038410428764, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038523674974, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038410428764, language=EN, stringName=Yufan MA, firstName=Yufan, middleName=null, lastName=MA, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211038607561055, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038410428764, language=CN, stringName=马渝凡, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211038687252833, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038758556003, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038687252833, language=EN, stringName=Bingqiao WANG, firstName=Bingqiao, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211038817276260, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038687252833, language=CN, stringName=王柄乔, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211038913745254, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038989242728, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038913745254, language=EN, stringName=Sen LIN, firstName=Sen, middleName=null, lastName=LIN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211039056351593, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038913745254, language=CN, stringName=林森, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211039127654763, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=yangqwmlys@tmmu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1322211039203152237, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211039127654763, language=EN, stringName=Qingwu YANG, firstName=Qingwu, middleName=null, lastName=YANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211039270261102, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211039127654763, language=CN, stringName=杨清武, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])])], keywords=[Keyword(id=1322211039379313007, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, orderNo=1, keyword=novel phenothiazine derivative), Keyword(id=1322211039446421872, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, orderNo=2, keyword=intracerebral hemorrhage), Keyword(id=1322211039513530737, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, orderNo=3, keyword=ferroptosis), Keyword(id=1322211039580639602, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, orderNo=4, keyword=inflammation), Keyword(id=1322211039664525683, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, orderNo=1, keyword=新型吩噻嗪衍生物), Keyword(id=1322211039760994676, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, orderNo=2, keyword=脑出血), Keyword(id=1322211039836492149, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, orderNo=3, keyword=铁死亡), Keyword(id=1322211039907795318, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, orderNo=4, keyword=炎症)], refs=[Reference(id=1322211043053523337, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1056/NEJMra2201449, pmid=null, pmcid=null, year=2022, volume=387, issue=17, pageStart=1589, pageEnd=1596, url=null, language=null, rfNumber=1, rfOrder=0, authorNames=SHETH K N, journalName=N Engl J Med, refType=null, unstructuredReference=SHETH K N. Spontaneous intracerebral hemorrhage［J］. N Engl J Med，2022，387（17）：1589-1596., articleTitle=Spontaneous intracerebral hemorrhage, refAbstract=null), Reference(id=1322211043133215114, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1001/jamaneurol.2021.0925, pmid=null, pmcid=null, year=2021, volume=78, issue=7, pageStart=809, pageEnd=816, url=null, language=null, rfNumber=2, rfOrder=1, authorNames=MURTHY S B, ZHANG C N, DIAZ I, journalName=JAMA Neurol, refType=null, unstructuredReference=MURTHY S B，ZHANG C N，DIAZ I，et al. Association between intracerebral hemorrhage and subsequent arterial ischemic events in participants from 4 population-based cohort studies［J］. JAMA Neurol，2021，78（7）：809-816., articleTitle=Association between intracerebral hemorrhage and subsequent arterial ischemic events in participants from 4 population-based cohort studies, refAbstract=null), Reference(id=1322211043191935371, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1172/JCI172841, pmid=null, pmcid=null, year=2024, volume=134, issue=10, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=3, rfOrder=2, authorNames=DUPRÉ N, DRIEU A, JOUTEL A, journalName=J Clin Invest, refType=null, unstructuredReference=DUPRÉ N，DRIEU A，JOUTEL A. Pathophysiology of cerebral small vessel disease：a journey through recent discoveries［J］. J Clin Invest，2024，134（10）：e172841., articleTitle=Pathophysiology of cerebral small vessel disease：a journey through recent discoveries, refAbstract=null), Reference(id=1322211043250655628, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.3390/cells12010090, pmid=null, pmcid=null, year=2022, volume=12, issue=1, pageStart=90, pageEnd=null, url=null, language=null, rfNumber=4, rfOrder=3, authorNames=SUN Y Y, LI Q, GUO H X, journalName=Cells, refType=null, unstructuredReference=SUN Y Y，LI Q，GUO H X，et al. Ferroptosis and iron metabolism after intracerebral hemorrhage［J］. Cells，2022，12（1）：90., articleTitle=Ferroptosis and iron metabolism after intracerebral hemorrhage, refAbstract=null), Reference(id=1322211043321958797, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41419-020-2298-2, pmid=null, pmcid=null, year=2020, volume=11, issue=2, pageStart=88, pageEnd=null, url=null, language=null, rfNumber=5, rfOrder=4, authorNames=LI J, CAO F, YIN H L, journalName=Cell Death Disease, refType=null, unstructuredReference=LI J，CAO F，YIN H L，et al. Ferroptosis：past，present and future ［J］. Cell Death Disease，2020，11（2）：88., articleTitle=Ferroptosis：past，present and future, refAbstract=null), Reference(id=1322211043405844878, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.3389/fnmol.2020.00110, pmid=null, pmcid=null, year=2020, volume=13, issue=null, pageStart=110, pageEnd=null, url=null, language=null, rfNumber=6, rfOrder=5, authorNames=CHEN J H, WANG Y H, WU J Y, journalName=Front Mol Neurosci, refType=null, unstructuredReference=CHEN J H，WANG Y H，WU J Y，et al. The potential value of targeting ferroptosis in early brain injury after acute CNS disease［J］. Front Mol Neurosci，2020，13：110., articleTitle=The potential value of targeting ferroptosis in early brain injury after acute CNS disease, refAbstract=null), Reference(id=1322211043477148047, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/j.cell.2012.03.042, pmid=null, pmcid=null, year=2012, volume=149, issue=5, pageStart=1060, pageEnd=1072, url=null, language=null, rfNumber=7, rfOrder=6, authorNames=DIXON S J, LEMBERG K M, LAMPRECHT M R, journalName=Cell, refType=null, unstructuredReference=DIXON S J，LEMBERG K M，LAMPRECHT M R，et al. Ferroptosis：an iron-dependent form of nonapoptotic cell death［J］. Cell，2012，149（5）：1060-1072., articleTitle=Ferroptosis：an iron-dependent form of nonapoptotic cell death, refAbstract=null), Reference(id=1322211043548451216, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1021/acschembio.7b00730, pmid=null, pmcid=null, year=2017, volume=12, issue=10, pageStart=2538, pageEnd=2545, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=SHAH R, MARGISON K, PRATT D A, journalName=ACS Chem Biol, refType=null, unstructuredReference=SHAH R，MARGISON K，PRATT D A. The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death［J］. ACS Chem Biol，2017，12（10）：2538-2545., articleTitle=The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death, refAbstract=null), Reference(id=1322211043615560081, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/j.brainresbull.2021.11.014, pmid=null, pmcid=null, year=2022, volume=178, issue=null, pageStart=144, pageEnd=154, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=WEI Y F, SONG X X, GAO Y, journalName=Brain Res Bull, refType=null, unstructuredReference=WEI Y F，SONG X X，GAO Y，et al. Iron toxicity in intracerebral hemorrhage：physiopathological and therapeutic implications［J］. Brain Res Bull，2022，178：144-154., articleTitle=Iron toxicity in intracerebral hemorrhage：physiopathological and therapeutic implications, refAbstract=null), Reference(id=1322211043686863250, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/j.ejmech.2020.112842, pmid=null, pmcid=null, year=2021, volume=209, issue=null, pageStart=112842, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=YANG W, LIU X L, SONG C L, journalName=Eur J Med Chem, refType=null, unstructuredReference=YANG W，LIU X L，SONG C L，et al. Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model［J］. Eur J Med Chem，2021，209：112842., articleTitle=Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model, refAbstract=null), Reference(id=1322211043762360723, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1007/s13311-019-00821-5, pmid=null, pmcid=null, year=2020, volume=17, issue=3, pageStart=1170, pageEnd=1183, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=YAN J, ZUO G, SHERCHAN P, journalName=Neurotherapeutics, refType=null, unstructuredReference=YAN J，ZUO G，SHERCHAN P，et al. CCR1 activation promotes neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after intracerebral hemorrhage in mice［J］. Neurotherapeutics，2020，17（3）：1170-1183., articleTitle=CCR1 activation promotes neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after intracerebral hemorrhage in mice, refAbstract=null), Reference(id=1322211043821080980, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.14336/AD.2023.0507, pmid=null, pmcid=null, year=2024, volume=15, issue=3, pageStart=1384, pageEnd=1397, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=CHEN R, XIE Q, XIE L X, journalName=Aging Dis, refType=null, unstructuredReference=CHEN R，XIE Q，XIE L X，et al. Thioredoxin1 binding metastasis-associated lung adenocarcinoma transcript 1 attenuates inflammation and apoptosis after intracerebral hemorrhage［J］. Aging Dis，2024，15（3）：1384-1397., articleTitle=Thioredoxin1 binding metastasis-associated lung adenocarcinoma transcript 1 attenuates inflammation and apoptosis after intracerebral hemorrhage, refAbstract=null), Reference(id=1322211043892384149, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.12659/PJR.892146, pmid=null, pmcid=null, year=2015, volume=80, issue=null, pageStart=40, pageEnd=50, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=ZIMNY A, NESKA-MATUSZEWSKA M, BLADOWSKA J, journalName=Pol J Radiol, refType=null, unstructuredReference=ZIMNY A，NESKA-MATUSZEWSKA M，BLADOWSKA J，et al. Intracranial lesions with low signal intensity on T2-weighted MR images—review of pathologies ［J］. Pol J Radiol，2015，80：40-50., articleTitle=Intracranial lesions with low signal intensity on T2-weighted MR images—review of pathologies, refAbstract=null), Reference(id=1322211043951104406, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/j.phrs.2023.106912, pmid=null, pmcid=null, year=2023, volume=196, issue=null, pageStart=106912, pageEnd=null, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=REN H L, PAN Y, WANG D N, journalName=Pharmacol Res, refType=null, unstructuredReference=REN H L，PAN Y，WANG D N，et al. CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage［J］. Pharmacol Res，2023，196：106912., articleTitle=CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage, refAbstract=null), Reference(id=1322211044034990487, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1186/s12974-018-1140-6, pmid=null, pmcid=null, year=2018, volume=15, issue=1, pageStart=106, pageEnd=null, url=null, language=null, rfNumber=15, rfOrder=14, authorNames=CHEN S P, ZHAO L H, SHERCHAN P, journalName=J Neuroinflamm, refType=null, unstructuredReference=CHEN S P，ZHAO L H，SHERCHAN P，et al. Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice［J］. J Neuroinflamm，2018，15（1）：106., articleTitle=Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice, refAbstract=null), Reference(id=1322211044097905048, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/nprot.2008.73, pmid=null, pmcid=null, year=2008, volume=3, issue=null, pageStart=1101, pageEnd=1108, url=null, language=null, rfNumber=16, rfOrder=15, authorNames=SCHMITTGEN T D, LIVAK K J, journalName=Nat Protoc, refType=null, unstructuredReference=SCHMITTGEN T D，LIVAK K J. Analyzing real-time PCR data by the comparative CT method［J］. Nat Protoc，2008，3：1101-1108., articleTitle=Analyzing real-time PCR data by the comparative CT method, refAbstract=null), Reference(id=1322211044169208217, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1007/s12264-023-01118-6, pmid=null, pmcid=null, year=2024, volume=40, issue=3, pageStart=401, pageEnd=414, url=null, language=null, rfNumber=17, rfOrder=16, authorNames=ZHANG X Y, ZHANG Y, SU Q Y, journalName=Neurosci Bull, refType=null, unstructuredReference=ZHANG X Y，ZHANG Y，SU Q Y，et al. Ion channel dysregulation following intracerebral hemorrhage［J］. Neurosci Bull，2024，40（3）：401-414., articleTitle=Ion channel dysregulation following intracerebral hemorrhage, refAbstract=null), Reference(id=1322211044232122778, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41422-020-00441-1, pmid=null, pmcid=null, year=2021, volume=31, issue=2, pageStart=107, pageEnd=125, url=null, language=null, rfNumber=18, rfOrder=17, authorNames=TANG D L, CHEN X, KANG R, journalName=Cell Res, refType=null, unstructuredReference=TANG D L，CHEN X，KANG R，et al. Ferroptosis：molecular mechanisms and health implications［J］. Cell Res，2021，31（2）：107-125., articleTitle=Ferroptosis：molecular mechanisms and health implications, refAbstract=null), Reference(id=1322211044316008859, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1002/advs.202300325, pmid=null, pmcid=null, year=2023, volume=10, issue=24, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=19, rfOrder=18, authorNames=WANG Y M, WU S, LI Q, journalName=Adv Sci, refType=null, unstructuredReference=WANG Y M，WU S，LI Q，et al. Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes［J］. Adv Sci，2023，10（24）：e2300325., articleTitle=Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes, refAbstract=null), Reference(id=1322211044425060764, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1021/acschemneuro.2c00308, pmid=null, pmcid=null, year=2023, volume=14, issue=6, pageStart=1071, pageEnd=1079, url=null, language=null, rfNumber=20, rfOrder=19, authorNames=CHENG Y J, ZHANG Z Q, TANG H, journalName=ACS Chem Neurosci, refType=null, unstructuredReference=CHENG Y J，ZHANG Z Q，TANG H，et al. Mitochondrial inhibitor rotenone triggers and enhances neuronal ferroptosis following intracerebral hemorrhage［J］. ACS Chem Neurosci，2023，14（6）：1071-1079., articleTitle=Mitochondrial inhibitor rotenone triggers and enhances neuronal ferroptosis following intracerebral hemorrhage, refAbstract=null), Reference(id=1322211044487975325, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1161/STROKEAHA. 116.015609, pmid=null, pmcid=null, year=2017, volume=48, issue=4, pageStart=1033, pageEnd=1043, url=null, language=null, rfNumber=21, rfOrder=20, authorNames=ZILLE M, KARUPPAGOUNDER S S, CHEN Y X, journalName=Stroke, refType=null, unstructuredReference=ZILLE M，KARUPPAGOUNDER S S，CHEN Y X，et al. Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis［J］. Stroke，2017，48（4）：1033-1043., articleTitle=Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis, refAbstract=null), Reference(id=1322211044567667102, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1136/svn-2018-000205, pmid=null, pmcid=null, year=2019, volume=4, issue=2, pageStart=93, pageEnd=95, url=null, language=null, rfNumber=22, rfOrder=21, authorNames=WAN J R, REN H L, WANG J, journalName=Stroke Vasc Neurol, refType=null, unstructuredReference=WAN J R，REN H L，WANG J. Iron toxicity，lipid peroxidation and ferroptosis after intracerebral haemorrhage［J］. Stroke Vasc Neurol，2019，4（2）：93-95., articleTitle=Iron toxicity，lipid peroxidation and ferroptosis after intracerebral haemorrhage, refAbstract=null), Reference(id=1322211044638970271, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/j.expneurol. 2024.114961, pmid=null, pmcid=null, year=2024, volume=382, issue=null, pageStart=114961, pageEnd=null, url=null, language=null, rfNumber=23, rfOrder=22, authorNames=SUN K Y, BAI X Y, ZHANG L, journalName=Exp Neurol, refType=null, unstructuredReference=SUN K Y，BAI X Y，ZHANG L，et al. A new strategy for the treatment of intracerebral hemorrhage：ferroptosis［J］. Exp Neurol，2024，382：114961., articleTitle=A new strategy for the treatment of intracerebral hemorrhage：ferroptosis, refAbstract=null), Reference(id=1322211044710273440, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41580-024-00703-5, pmid=null, pmcid=null, year=2024, volume=25, issue=null, pageStart=424, pageEnd=442, url=null, language=null, rfNumber=24, rfOrder=23, authorNames=DIXON S J, OLZMANN J A, journalName=Nat Rev Mol Cell Biol, refType=null, unstructuredReference=DIXON S J，OLZMANN J A. The cell biology of ferroptosis［J］. Nat Rev Mol Cell Biol，2024，25：424-442., articleTitle=The cell biology of ferroptosis, refAbstract=null), Reference(id=1322211044773188001, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41580-020-00324-8, pmid=null, pmcid=null, year=2021, volume=22, issue=4, pageStart=266, pageEnd=282, url=null, language=null, rfNumber=25, rfOrder=24, authorNames=JIANG X J, STOCKWELL B R, CONRAD M, journalName=Nat Rev Mol Cell Biol, refType=null, unstructuredReference=JIANG X J，STOCKWELL B R，CONRAD M. Ferroptosis：mechanisms，biology and role in disease［J］. Nat Rev Mol Cell Biol，2021，22（4）：266-282., articleTitle=Ferroptosis：mechanisms，biology and role in disease, refAbstract=null), Reference(id=1322211044836102562, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1016/S1474-4422（19）30078-X, pmid=null, pmcid=null, year=2019, volume=18, issue=11, pageStart=1058, pageEnd=1066, url=null, language=null, rfNumber=26, rfOrder=25, authorNames=SHI K B, TIAN D C, LI Z G, journalName=Lancet Neurol, refType=null, unstructuredReference=SHI K B，TIAN D C，LI Z G，et al. Global brain inflammation in stroke［J］. Lancet Neurol，2019，18（11）：1058-1066., articleTitle=Global brain inflammation in stroke, refAbstract=null), Reference(id=1322211044903211427, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.16016/j.2097-0927.202312135, pmid=null, pmcid=null, year=2024, volume=46, issue=11, pageStart=1254, pageEnd=1264, url=null, language=null, rfNumber=27, rfOrder=26, authorNames=张忠意, 唐于广, 代金雨, journalName=陆军军医大学学报, refType=null, unstructuredReference=张忠意，唐于广，代金雨，等. G蛋白偶联受体39在小鼠脑出血后脑损伤的作用及机制研究［J］. 陆军军医大学学报，2024，46（11）：1254-1264., articleTitle=G蛋白偶联受体39在小鼠脑出血后脑损伤的作用及机制研究, refAbstract=null), Reference(id=1322211044970320292, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.16016/j.2097-0927.202312135, pmid=null, pmcid=null, year=2024, volume=46, issue=11, pageStart=1254, pageEnd=1264, url=null, language=null, rfNumber=27, rfOrder=27, authorNames=ZHANG Z Y, TANG Y G, DAI J Y, journalName=J Amry Med Univ, refType=null, unstructuredReference=ZHANG Z Y，TANG Y G，DAI J Y，et al. Role and mechanisms of G-protein-coupled receptor 39 in brain injury after intracerebral hemorrhage in mice［J］. J Amry Med Univ，2024，46（11）：1254-1264., articleTitle=Role and mechanisms of G-protein-coupled receptor 39 in brain injury after intracerebral hemorrhage in mice, refAbstract=null), Reference(id=1322211045029040549, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41419-023-05716-0, pmid=null, pmcid=null, year=2023, volume=14, issue=3, pageStart=205, pageEnd=null, url=null, language=null, rfNumber=28, rfOrder=28, authorNames=CHEN Y, FANG Z M, YI X, journalName=Cell Death Dis, refType=null, unstructuredReference=CHEN Y，FANG Z M，YI X，et al. The interaction between ferroptosis and inflammatory signaling pathways［J］. Cell Death Dis，2023，14（3）：205., articleTitle=The interaction between ferroptosis and inflammatory signaling pathways, refAbstract=null), Reference(id=1322211045083566502, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1186/s12951-024-02560-y, pmid=null, pmcid=null, year=2024, volume=22, issue=1, pageStart=291, pageEnd=null, url=null, language=null, rfNumber=29, rfOrder=29, authorNames=WANG Y, LIU Z H, LI L Y, journalName=J Nanobiotechnology, refType=null, unstructuredReference=WANG Y，LIU Z H，LI L Y，et al. Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke［J］. J Nanobiotechnology，2024，22（1）：291., articleTitle=Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke, refAbstract=null), Reference(id=1322211045146481063, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, doi=10.1038/s41467-025-56097-1, pmid=null, pmcid=null, year=2025, volume=16, issue=1, pageStart=699, pageEnd=null, url=null, language=null, rfNumber=30, rfOrder=30, authorNames=YOON S H, KIM C Y, LEE E, journalName=Nat Commun, refType=null, unstructuredReference=YOON S H，KIM C Y，LEE E，et al. Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice［J］. Nat Commun，2025，16（1）：699., articleTitle=Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])], figs=[ArticleFig(id=1322211040042013047, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=xnBjOv4DrwjApbCi3pmnYQ==, figureFileBig=8bvm11hRFNjFWQ1b9ezXbg==, tableContent=null), ArticleFig(id=1322211040125899128, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图1, caption=DA414的化学结构, figureFileSmall=xnBjOv4DrwjApbCi3pmnYQ==, figureFileBig=8bvm11hRFNjFWQ1b9ezXbg==, tableContent=null), ArticleFig(id=1322211040344002937, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=79EGcDREFZh6Kqi8oFeU4A==, figureFileBig=Z4nfwFkMCUmmSFjlmiXAgQ==, tableContent=null), ArticleFig(id=1322211040411111802, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图2, caption=DA414处理后ICH血肿体积变化情况（n=4，x¯±s）

a：P<0.05，b：P<0.01，与模型组相比A、B：连续5 d予以不同剂量DA414处理后的脑组织切片测量血肿体积及统计分析结果；C、D：MRI梯度回波序列T2加权相评估病变的体积及统计分析结果

, figureFileSmall=79EGcDREFZh6Kqi8oFeU4A==, figureFileBig=Z4nfwFkMCUmmSFjlmiXAgQ==, tableContent=null), ArticleFig(id=1322211040474026363, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=FBWl1pvgL+ZFtdq84LF+hQ==, figureFileBig=B488j4BaimdLdHmM71ayYA==, tableContent=null), ArticleFig(id=1322211040541135228, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图3, caption=DA414处理后大鼠行为学评估（n=10，x¯±s）

a：P<0.001，与假手术组比较；b：P<0.001，与第3天5 mg/（kg·d） DA414组比较；c：P<0.05，与模型组比较；d：P<0.01，与5 mg/（kg·d） DA414组比较A：连续腹腔注射不同剂量的DA414后第1、3、7天的改良神经功能评分；B：ICH模型DA414处理后第1、3、7天的左转率

, figureFileSmall=FBWl1pvgL+ZFtdq84LF+hQ==, figureFileBig=B488j4BaimdLdHmM71ayYA==, tableContent=null), ArticleFig(id=1322211040608244093, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=HNQDK3F1MTFfsYmhz/lshw==, figureFileBig=HUtOsUXWjzpGVbKP8nEdmA==, tableContent=null), ArticleFig(id=1322211040683741566, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图4, caption=DA414处理后铁死亡关键分子GPX4的变化情况（n=3，x¯±s）

A、B：Western blot实验检测DA414处理后ICH大鼠的GPX4的表达水平及统计分析结果　a：P<0.01，与模型组比较

, figureFileSmall=HNQDK3F1MTFfsYmhz/lshw==, figureFileBig=HUtOsUXWjzpGVbKP8nEdmA==, tableContent=null), ArticleFig(id=1322211040750850431, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=CVBXZk/2kFxNKfr6xLZM4g==, figureFileBig=L6uP7DFw/F4gxssU0jccwg==, tableContent=null), ArticleFig(id=1322211042407600512, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图5, caption=DA414对小胶质细胞活化的影响（n=3，x¯±s）

a：P<0.001，与假手术组比较；b：P<0.001，c：P<0.01，与模型组比较A：ICH后5 d周围血肿IBA1（红色）和 CD68（绿色）的代表性双免疫荧光染色；B：IBA1阳性细胞数；C：CD68细胞阳性细胞数；D：IBA1与CD68的双阳性细胞数

, figureFileSmall=CVBXZk/2kFxNKfr6xLZM4g==, figureFileBig=L6uP7DFw/F4gxssU0jccwg==, tableContent=null), ArticleFig(id=1322211042483097985, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=W4g2qlKOAhqUbmlP+Xt2Pw==, figureFileBig=JXweS8l0WleqzlRMDAO+Zg==, tableContent=null), ArticleFig(id=1322211042562789762, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图6, caption=DA414对ICH后NLRP3炎症小体通路关键分子及炎症因子mRNA表达影响（n=3，x¯±s）

a：P<0.05，b：P<0.01，与模型组比较A~I：RT-qPCR分析NLRP3、Caspase-1、IL-1β、IL-18、TLR4、TNF-α、IL-6、IL-4及IL-10的mRNA修饰水平变化

, figureFileSmall=W4g2qlKOAhqUbmlP+Xt2Pw==, figureFileBig=JXweS8l0WleqzlRMDAO+Zg==, tableContent=null), ArticleFig(id=1322211042625704323, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=o+Dm/5vjkdigNgpGSfB9Mg==, figureFileBig=Zs0OQumjbEwpXEd8Hbx3xQ==, tableContent=null), ArticleFig(id=1322211042697007492, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=图7, caption=DA414处理后体内重要脏器的安全性评估

A：DA414处理后大鼠脑和肝脏的伊文思蓝染色；B：DA414处理后各组肝脏、肾脏、心脏的HE染色

, figureFileSmall=o+Dm/5vjkdigNgpGSfB9Mg==, figureFileBig=Zs0OQumjbEwpXEd8Hbx3xQ==, tableContent=null), ArticleFig(id=1322211042755727749, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列（5'→3'）
GAPDH上游：TCCCTCAAGATTGTCAGCAA
下游：AGATCCACAACGGATACATT
NLRP3上游：GATTTCTCCACAACTCACCCAA
下游：AGTCTGGAAGAACGAGCAACA
TLR4上游：CCGCTCTGGCATCATCTTCA
下游：TCCCACTCGAGGTAGGTGTT
IL-1β上游：GTGGAGCTTCCAGGATGAGG
下游：CACACACTAGCAGGTCGTCA
IL-18上游：TGGCTGCCATACCAGAAGAA
下游：TGCCAAAGTGGTCTGATTCCA
Caspase-1上游：GACCGAGTGGTTCCCTCAAG
下游：GACGTGTACGAGTGGGTGTT
IL-10上游：AAAGCAAGGCAGTGGAGCAG
下游：AGTAGATGCCGGGTGGTTCA
IL-6上游：AGGAGTGGCTAAGGACCAAGACC
下游：TGCCGAGTAGACCTCATAGTGACC
TNF-α上游：GCATGATCCGAGATGTGGAACTGG
下游：CGCCACGAGCAGGAATGAGAAG
TL-4上游：CTTACGGCAACAAGGAACACCA
下游：CTTCAAGCACGGAGGTACATCAC
), ArticleFig(id=1322211042822836614, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=表1, caption=

基因引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列（5'→3'）
GAPDH上游：TCCCTCAAGATTGTCAGCAA
下游：AGATCCACAACGGATACATT
NLRP3上游：GATTTCTCCACAACTCACCCAA
下游：AGTCTGGAAGAACGAGCAACA
TLR4上游：CCGCTCTGGCATCATCTTCA
下游：TCCCACTCGAGGTAGGTGTT
IL-1β上游：GTGGAGCTTCCAGGATGAGG
下游：CACACACTAGCAGGTCGTCA
IL-18上游：TGGCTGCCATACCAGAAGAA
下游：TGCCAAAGTGGTCTGATTCCA
Caspase-1上游：GACCGAGTGGTTCCCTCAAG
下游：GACGTGTACGAGTGGGTGTT
IL-10上游：AAAGCAAGGCAGTGGAGCAG
下游：AGTAGATGCCGGGTGGTTCA
IL-6上游：AGGAGTGGCTAAGGACCAAGACC
下游：TGCCGAGTAGACCTCATAGTGACC
TNF-α上游：GCATGATCCGAGATGTGGAACTGG
下游：CGCCACGAGCAGGAATGAGAAG
TL-4上游：CTTACGGCAACAAGGAACACCA
下游：CTTCAAGCACGGAGGTACATCAC
), ArticleFig(id=1322211042889945479, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
指标假手术组模型组10 mg/（kg·d） DA414组P1P2
AST89.85±11.1091.45±12.3796.55±14.060.790.65
ALT40.57±3.4139.18±2.4839.23±6.030.990.99
DBIL0.65±0.150.55±0.140.50±0.110.690.88
TBIL1.43±0.771.55±2.051.28±1.500.290.36
GLB33.89±1.7332.22±0.8430.05±1.640.150.25
ALB30.93±0.8131.58±0.8629.60±1.260.960.47
TP64.82±1.1863.80±1.3959.65±2.680.620.72
UREA7.53±1.179.75±0.768.75±0.760.650.77
CREA50.70±4.6851.77±12.0056.55±6.530.970.92
UA179.83±34.37210.83±91.93184.83±52.420.690.77
), ArticleFig(id=1322211042961248648, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, language=CN, label=表2, caption=

肝肾功能检测（n=3，x¯±s）

, figureFileSmall=null, figureFileBig=null, tableContent=
指标假手术组模型组10 mg/（kg·d） DA414组P1P2
AST89.85±11.1091.45±12.3796.55±14.060.790.65
ALT40.57±3.4139.18±2.4839.23±6.030.990.99
DBIL0.65±0.150.55±0.140.50±0.110.690.88
TBIL1.43±0.771.55±2.051.28±1.500.290.36
GLB33.89±1.7332.22±0.8430.05±1.640.150.25
ALB30.93±0.8131.58±0.8629.60±1.260.960.47
TP64.82±1.1863.80±1.3959.65±2.680.620.72
UREA7.53±1.179.75±0.768.75±0.760.650.77
CREA50.70±4.6851.77±12.0056.55±6.530.970.92
UA179.83±34.37210.83±91.93184.83±52.420.690.77
)], attaches=null, journal=Journal(id=1319372634082869396, delFlag=0, nameCn=陆军军医大学学报, nameEn=Journal of Army Medical University, nameHistory1=null, nameHistory2=null, issn=2097-0927, eissn=null, cn=50-1223/R, coden=null, periodic=3, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=zdiTazv9TbsMJqLaCJ/k7A==, journalPrice=null, startedYear=null, abbrevIsoEn=Journal of Army Medical University, journalRemark=null, publicationField=null, createdTime=1792492548725, updatedTime=1792745216517, createdBy=18614031015, updatedBy=13701087609, firstLetterCn=L, firstLetterEn=L, subjectCode=Medical and Pharmaceutical Sciences, subjectName=null, subjectCodeEn=Medical and Pharmaceutical Sciences, subjectNameEn=null, picCn=zdiTazv9TbsMJqLaCJ/k7A==, picEn=931BgeD2k9AIsc7QjHoQKg==, jcr=null, cjcr=null, exts=[JournalExt(id=1320432400862135101, language=CN, name=陆军军医大学学报, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1792745216813, updatedTime=1792745216813, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://ljjydx.portal.founderss.cn, submissionEditorUrl=https://journal.ids.fzyun.cn, submissionReviewUrl=https://ljjydx.portal.founderss.cn, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1320432400933438270, language=EN, name=Journal of Army Medical University, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1792745216830, updatedTime=1792745216830, createdBy=13701087609, updatedBy=13701087609, submissionGuidelinesUrl=, submissionAuthorUrl=https://ljjydx.portal.founderss.cn, submissionEditorUrl=https://journal.ids.fzyun.cn, submissionReviewUrl=https://ljjydx.portal.founderss.cn, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1319373162502258839, websiteList=[Website(id=1319376331821925278, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1319373162502258839, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/ljjydxxb/CN, language=CN, createTime=1792493430333, createBy=18614031015, updateTime=1792493552921, updateBy=18614031015, name=陆军军医大学学报-中文, tplId=1146099689490845704, title=陆军军医大学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1319376971570729589, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=articleTextType, value=kx, createTime=1792493582861, updateTime=1792493582861, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971549758066, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=banner, value=null, createTime=1792493582856, updateTime=1792493582856, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971591701112, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=grayFlag, value=0, createTime=1792493582866, updateTime=1792493582866, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971541369457, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=logo, value=https://castjournals.cast.org.cn/joweb/ljjydxxb/CN/file/pic?fileId=Mmvh7crXM7dcUwf9n9+ehg==, createTime=1792493582854, updateTime=1792493582854, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971608478330, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=minRunFlag, value=0, createTime=1792493582870, updateTime=1792493582870, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971562340980, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/ljjydxxb/CN/file/pic, createTime=1792493582859, updateTime=1792493582859, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971600089721, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=silenceFlag, value=0, createTime=1792493582868, updateTime=1792493582868, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971558146675, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1792493582858, updateTime=1792493582858, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971574923894, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=themeColor, value=null, createTime=1792493582862, updateTime=1792493582862, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376971583312503, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331821925278, code=themeStyle, value=null, createTime=1792493582864, updateTime=1792493582864, creator=18614031015, updator=18614031015)]), Website(id=1319376331905811365, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1319373162502258839, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/ljjydxxb/EN, language=EN, createTime=1792493430353, createBy=18614031015, updateTime=1792493548158, updateBy=18614031015, name=陆军军医大学学报-英文, tplId=1146101810881728533, title=Journal of Army Medical University, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1319376935873008230, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=articleTextType, value=kx, createTime=1792493574350, updateTime=1792493574350, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935843648099, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=banner, value=null, createTime=1792493574343, updateTime=1792493574343, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935902368361, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=grayFlag, value=0, createTime=1792493574357, updateTime=1792493574357, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935835259490, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=logo, value=https://castjournals.cast.org.cn/joweb/ljjydxxb/EN/file/pic?fileId=Mmvh7crXM7dcUwf9n9+ehg==, createTime=1792493574341, updateTime=1792493574341, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935914951275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=minRunFlag, value=0, createTime=1792493574360, updateTime=1792493574360, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935864619621, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/ljjydxxb/EN/file/pic, createTime=1792493574348, updateTime=1792493574348, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935906562666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=silenceFlag, value=0, createTime=1792493574358, updateTime=1792493574358, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935856231012, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1792493574346, updateTime=1792493574346, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935881396839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=themeColor, value=null, createTime=1792493574352, updateTime=1792493574352, creator=18614031015, updator=18614031015), WebsiteProps(id=1319376935889785448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1319376331905811365, code=themeStyle, value=null, createTime=1792493574354, updateTime=1792493574354, creator=18614031015, updator=18614031015)])], journalTitle=陆军军医大学学报, weixinUrl=null, journalUrl=https://aammt.tmmu.edu.cn/, iacademicId=null, status=1, seqNo=null, journalTitleEn=Journal of Army Medical University, journalPhotoCn=zdiTazv9TbsMJqLaCJ/k7A==, journalPhotoEn=931BgeD2k9AIsc7QjHoQKg==, journalFirstLetter=L, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false, interPubPlatform=, interPubPlatformUrl=null), detailUrlCn=https://castjournals.cast.org.cn/joweb/ljjydxxb/CN/10.16016/j.2097-0927.202501047, detailUrlEn=https://castjournals.cast.org.cn/joweb/ljjydxxb/EN/10.16016/j.2097-0927.202501047, pdfUrlCn=https://castjournals.cast.org.cn/joweb/ljjydxxb/CN/PDF/10.16016/j.2097-0927.202501047, pdfUrlEn=https://castjournals.cast.org.cn/joweb/ljjydxxb/EN/PDF/10.16016/j.2097-0927.202501047, aliStartDate=0, aliEndDate=0, collectionFlag=false, citedCount=null, citedUrl=null, previewStatus=0, delFlag=0, hasFullText=1, orderTime=1747238400000, fullTextJson=null, articleText=null, reference=null)
收藏切换
新型吩噻嗪衍生物DA414在大鼠脑出血中的作用及机制研究
收藏切换
PDF下载
马渝凡 , 王柄乔 , 林森 , 杨清武
陆军军医大学学报 | 基础医学 2025,47(9): 922-934
收起
收藏切换
陆军军医大学学报 |基础医学 2025 , 47 (9) : 922 -934
新型吩噻嗪衍生物DA414在大鼠脑出血中的作用及机制研究
全屏
[Author(id=1322211038410428764, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038523674974, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038410428764, language=EN, stringName=Yufan MA, firstName=Yufan, middleName=null, lastName=MA, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211038607561055, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038410428764, language=CN, stringName=马渝凡, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211038687252833, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038758556003, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038687252833, language=EN, stringName=Bingqiao WANG, firstName=Bingqiao, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211038817276260, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038687252833, language=CN, stringName=王柄乔, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211038913745254, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1322211038989242728, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038913745254, language=EN, stringName=Sen LIN, firstName=Sen, middleName=null, lastName=LIN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211039056351593, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211038913745254, language=CN, stringName=林森, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])]), Author(id=1322211039127654763, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=yangqwmlys@tmmu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1322211039203152237, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211039127654763, language=EN, stringName=Qingwu YANG, firstName=Qingwu, middleName=null, lastName=YANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1322211039270261102, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, authorId=1322211039127654763, language=CN, stringName=杨清武, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1322211038339125592, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, xref=1, ext=[AuthorCompanyExt(id=1322211038343319897, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China), AuthorCompanyExt(id=1322211038351708506, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322211034765578567, companyId=1322211038339125592, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆)])])]
马渝凡, 王柄乔, 林森, 杨清武
作者信息
  • 1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆
通讯作者:
杨清武，E-mail：
YANG Qingwu，E-mail：
作者简介:

同等贡献者

MA Yufan and WANG Bingqiao contributed equally to the article.

Effects and underlying mechanisms of novel phenothiazine derivative DA414 in rats with intracerebral hemorrhage
Yufan MA, Bingqiao WANG, Sen LIN, Qingwu YANG
Affiliations
  • 1Department of Neurology，Second Affiliated Hospital，Army Medical University （Third Military Medical University），Chongqing，China
出版时间: 2025-05-15 doi: 10.16016/j.2097-0927.202501047
文章导航
收藏切换
摘要
收起
目的

探讨新型吩噻嗪衍生物DA414对脑出血（intracerebral hemorrhage，ICH）大鼠的疗效及作用机制。

方法

雄性SD大鼠（8~10周龄，体质量250~300 g）按随机数字表法分为假手术组、模型组、5 mg/（kg·d） DA414组和10 mg/（kg·d）DA414组，每组20只。采用磁共振成像（magnetic resonance imaging， MRI）及组织切片定量分析ICH区域的大小及损伤程度；神经功能通过行为学进行评估；Western blot探讨DA414对铁死亡调节因子谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4） 的表达影响；多重荧光免疫组化对血肿周围组织小胶质细胞活化状态定量分析；RT-qPCR检测炎症小体通路（NLRP3、Caspase-1、IL-1β）及促炎（IL-18、TLR4、IL-6、TNF-α）和抗炎（IL-4、IL-10）细胞因子的mRNA表达水平。通过伊文思蓝染色评估血脑屏障（blood-brain barrier，BBB）的完整性，HE染色和临床生化检验评估DA414对肝脏、肾脏和心脏的安全性。

结果

DA414显著促进了ICH后血肿的吸收，减少神经损伤，并显著改善神经功能评分。与模型组相比，DA414处理能够显著上调铁死亡调节因子GPX4的水平（P<0.01）；且显著抑制了ICH后小胶质活化（P<0.001）；RT-qPCR进一步证实其下调炎症小体通路NLRP3（P<0.01）、Caspase-1（P<0.01）、IL-1β（P<0.01）及促炎因子IL-18（P<0.01）、TLR4（P<0.05）、IL-6（P<0.05）、TNF-α（P<0.01），同时上调抗炎细胞因子IL-4、IL-10 mRNA表达（P<0.05），提示其神经保护作用可能通过调节铁死亡及炎症双重机制实现。安全性评估进一步表明DA414干预对大鼠BBB无明显影响，且其对肝脏、肾脏、心脏也无明显损伤。

结论

DA414通过靶向抑制铁死亡并调节炎症反应，在ICH模型中表现出显著神经保护效应，为ICH治疗提供实验基础。

新型吩噻嗪衍生物  /  脑出血  /  铁死亡  /  炎症
Objective‍

To explore the efficacy and action mechanism of a novel phenothiazine derivative, DA414, in rats with intracerebral hemorrhage (ICH).

Methods‍

Male Sprague-Dawley (SD) rats (aged 8~10 weeks, weighing 250~300 g) were randomly divided into sham operation, model, and low and high dose DA414 groups [5 and 10 mg/(kg·d)], with20 animals per group. The size and extent of injury in the ICH area were measured by magnetic resonance imaging (MRI) and histopathological slices. Neurological function was evaluated with a behavioral grading system. Western blotting was used to detect the expression of ferroptosis-related factor, glutathione peroxidase 4 (GPX4). Multiplex immunohistochemistry was employed to quantitatively evaluate microglial activation in perihematomal tissue. RT-qPCR was applied to measure the mRNA expression levels of NLRP3 inflammasome components (NLRP3, Caspase-1, IL-1β), pro-inflammatory (IL-18, TLR4, IL-6, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10). The integrity of the blood-brain barrier (BBB) was assessed by Evans blue staining, and the biosafety of DA414 for the liver, kidneys and heart was assessed by HE staining and clinical biochemical tests.

Results‍

DA414 significantly promoted the absorption of hematoma, reduced neuronal injury, and improved neurological function scores. DA414 significantly up-regulated the ferroptosis regulatory factor GPX4 (P<0.01), and also significantly inhibited the activation of microglia after ICH (P<0.001). RT-qPCR indicated that DA414 treatment resulted in down-regulation of mRNA expression in the inflammasome pathway (NLRP3, Caspase-1, IL-1β, all P<0.01) and pro-inflammatory cytokines (TLR4, IL-6, both P<0.05; IL-18, TNF-α, both P<0.01) and up-regulation of anti-inflammatory cytokines (IL-4, IL-10, both P<0.05), suggesting that DA414 exerts its neuroprotective effect probably by regulating ferroptosis and inflammation. Safety assessment revealed that DA414 had no significant effect on BBB integrity or damage to the liver, kidneys, and heart in rats.

Conclusion‍

DA414 exerts significant neuroprotective effects in ICH model by targeted inhibition for ferroptosis and modulating inflammatory response. Our study provides an experimental foundation for ICH treatment.

novel phenothiazine derivative  /  intracerebral hemorrhage  /  ferroptosis  /  inflammation
马渝凡, 王柄乔, 林森, 杨清武. 新型吩噻嗪衍生物DA414在大鼠脑出血中的作用及机制研究. 陆军军医大学学报, 2025 , 47 (9) : 922 -934 . DOI: 10.16016/j.2097-0927.202501047
Yufan MA, Bingqiao WANG, Sen LIN, Qingwu YANG. Effects and underlying mechanisms of novel phenothiazine derivative DA414 in rats with intracerebral hemorrhage[J]. Journal of Army Medical University, 2025 , 47 (9) : 922 -934 . DOI: 10.16016/j.2097-0927.202501047
正文
收起
脑出血（intracerebral hemorrhage，ICH）是指脑实质内血管破裂而引发的出血，占所有脑卒中的20%~30%［1］。ICH具有起病急骤、病情进展迅速、高致死率和高致残率的特点，其急性期病死率可达30%~40%［2］。在幸存者中，大多数患者会遗留运动功能障碍、认知障碍及言语或吞咽困难等长期后遗症。ICH主要通过机械性压迫、细胞毒性作用、代谢亢进、炎症反应及氧化应激等病理过程，引发原发性和继发性脑损伤，导致脑组织的严重损害［3］。目前，ICH的治疗主要包括早期的手术干预和后期的药物治疗，但整体疗效仍然有限。因此，探索更有效的治疗策略以改善患者的预后仍是当前研究的重要方向。
铁死亡在ICH的病理机制中发挥着关键作用，出血后血红蛋白释放过量的游离铁产生羟基自由基，从而导致细胞凋亡和坏死、灰质损伤和脑血屏障 （blood-brain barrier，BBB）破坏［4］。此外，铁进入神经元可诱导以脂质过氧化为核心的铁死亡［5］。最新研究显示，铁死亡抑制剂能够有效减轻ICH患者的大脑继发性损伤。例如，铁抑素-1（ferrostatin-1，Fer-1）已被证明可通过减少血肿周围脑组织的铁积累来显著减轻神经损伤 ［6］。铁死亡这一概念由DIXON等［7］于2012年首次提出，并被细胞死亡命名委员会明确定义为一种由氧化应激引发的调控性细胞死亡（regulated cell death，RCD），其分子机制受谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）调控。该过程的主要生化特征包括铁离子蓄积和脂质过氧化的发生。上述研究提示，针对铁死亡的干预措施可能为治疗ICH相关脑损伤提供一种新的策略。SHAH等［8］发现，多种二芳胺类自由基捕获抗氧化剂（如吩噻嗪）具有铁死亡抑制活性。吩噻嗪衍生物是一类能够抑制脂质过氧化的抗氧化剂［9］。2-（1-（4-（4-甲基哌嗪-1-基）苯基）乙基）-10H-吩噻嗪（DA414，又称为化合物51）是一种新型的吩噻嗪衍生物，已被证实能够穿过BBB，并在缺血性脑卒中大鼠模型中显示出显著的治疗效果［10］。同时，该药物已进入Ⅰ期临床研究阶段（CTR20240630）。因此，本研究旨在探讨DA414在ICH诱导的脑损伤中对神经功能的保护作用及其初步机制。
1　材料与方法
收起
1.1　实验动物
80只雄性SD大鼠（8~10周龄，体质量250~300 g），均购买自斯莱克景达实验动物公司。大鼠饲养于陆军军医大学第二附属医院动物中心，饲养期间提供充足的水和食物，室温20~25 ℃，相对湿度50%~60%，昼夜各半循环光照。所有程序和动物实验按照《中华人民共和国实验动物管理条例》，并通过陆军军医大学实验动物福利伦理委员会审批（AMUWEC20255341）。
1.2　试剂与仪器
2-（1-（4-（4-甲基哌嗪-1-基）苯基）乙基）-10H-吩噻嗪（DA414）由四川大学生物治疗国家重点实验室和上海医药股份有限公司合成，玉米油购自中国MCE公司，PBS与4%PFA购自中国川东化工，异氟烷购自中国瑞沃德，乌拉坦购自德国默克生命科学有限公司，兔抗GPX4抗体购自英国Abcam公司，鼠抗GAPDH抗体购自美国Santa Cruz公司，兔抗CD68抗体购自美国Cell Signaling Technology公司，兔抗IBA1抗体购自日本wako公司，polymer-HRP羊抗鼠/兔二抗试剂盒、TYR-520 荧光染料、TYR-570 荧光染料购自中国艾方生物科技有限公司，山羊抗兔二抗、山羊抗鼠二抗购自美国Invitrogen公司，定量PCR专用反转录试剂盒PrimeScript™ RT reagent Kit with gDNA Eraser （Perfect Real Time）购自日本Takara公司，SYBR® Green Realtime PCR Master Mix 预混液购自日本Toyobo公司，超灵敏凝胶化学发光成像系统购自美国AcuronBio公司，核酸扩增分析仪（荧光）购自中国Bio-Rad公司，冰冻切片机购自德国Leica公司，共聚焦显微镜购自日本Olympus公司，7.0 T MRI小动物扫描仪购自德国Bruker公司。
1.3　动物模型的构建
1.3.1　自发性ICH模型的构建
如既往研究所述，断尾法获取的自体血通过立体定向注射到左侧纹状体区域来诱导ICH手术［11］ 。在手术过程中用异氟烷-氧混合物麻醉大鼠（4%用于诱导麻醉，1% 用于维持麻醉），并使用加热毯将体温维持在37 ℃左右。大鼠以俯卧位固定在立体定向头架上，以矢状位剪开头皮以暴露颅骨，直到前囟清晰可见。参照Paxinos大鼠脑立体定位图谱，以前囟点为三维坐标系原点，使用脑立体定位仪精确定位目标区域（坐标参数：X=+3.5 mm外侧向，Y=-0.2 mm前囟后侧向），接着使用直径0.6 mm的颅骨钻在目标位置钻孔（孔径1 mm），将连接微量注射器的针头（内装自体血液）插入至深度约5.5 mm 处。以10 μL/min的速率注入总体积为70 μL的自体血［12］。为防止血液回流可能导致的渗漏，在完成70 μL的自体血注射后，将针头再留置10 min，缓慢抽出，并缝合头皮切口。实验结束后让将大鼠放置在37 ℃的加热垫上完全恢复，并密切观察神经功能缺损症状。假手术组相较于实验组，没有血液注射这一操作，其余操作均保持一致。
1.3.2　实验药物
DA414为脂溶性药物，其化学结构如图1所示。玉米油是一种有效的脂类溶剂，具有无毒和无刺激性，能够溶解许多脂溶性强的化合物。鉴于玉米油作为药物载体具有良好的药物溶解度、化学稳定性及优化药代动力学特性的优势，本研究选择其作为DA414的溶剂载体。具体给药方案为：ICH模型成功构建30 min后，经腹腔注射途径给予DA414玉米油混悬液，以期通过提高生物利用度增强治疗效能。SD大鼠按随机数字表法分为4组：无处理对照组（假手术组）、ICH模型构建后玉米油处理组（模型组）、5 mg/（kg·d） DA414组和10 mg/（kg·d） DA414组，每组20只。通过腹腔注射连续给药5 d，其中DA414组分别按设定剂量给药，假手术组和模型组注射等体积玉米油溶剂。
1.3.3　实验样本分配方案
实验样本分配方案如下：①脑损伤体积评估：模型组、5 mg/（kg·d） DA414组和10 mg/（kg·d） DA414各取4只大鼠，通过磁共振成像（magnetic resonance imaging， MRI）联合组织切片对血肿体积定量分析；②神经行为学评估：假手术组、模型组、5 mg/（kg·d） DA414组及10 mg/（kg·d） DA414组各取10只大鼠，实施神经功能评分及转角实验；③分子机制检测：模型组与10 mg/（kg·d） DA414组各取3只大鼠，开展Western blot及RT-qPCR检测铁死亡关键蛋白GPX4与炎症信号通路基因表达；④病理学分析：假手术组、模型组及10 mg/（kg·d） DA414组各取3只大鼠，采用多重免疫荧光共标记观察脑血肿区域IBA1+/CD68+细胞表型，并通过HE染色评估心、肝、肾重要脏器的病理损伤；⑤安全性评估：HE染色处理前取上述④中各组大鼠血液进行肝肾功能评估。
1.4　脑组织切片血肿体积测量
ICH 模型构建后5 d后，对各组大鼠腹腔注射20%乌拉坦溶液（以0.9%生理盐水配制，7 mL/kg）实施全身麻醉，待大鼠完全失去反应，经心脏灌注4 ℃预冷的PBS。将脑组织置于脑切片模具中制备连续冠状切片（厚度2 mm），并进行拍照处理。使用Image J软件测量各切片的ICH体积。
1.5　通过MRI评估ICH
由于本研究主要观察ICH后5 d亚急性早期，在此时期红细胞内的血红蛋白被氧化为正铁血红蛋白，具有顺磁性，在T2加权相下表现为低信号，而其中的水分表现为高信号，有助于出血病变的识别［13］。因此，本文中采用7.0 T MRI小动物扫描仪，通过T2加权相对血肿体积进行定量分析。其实验操作如下：利用异氟烷对各组大鼠进行麻醉（4.0%诱导麻醉，1.5%维持麻醉），利用四通道头部线圈完成头部的定位扫描，所有大鼠的成像方案为T2WI Turbo RARE序列（重复时间3 000 ms，回波时间45 ms）。视野为35 mm×35 mm，像素为256 mm×256 mm，片厚为0.5 mm，收集冠状位切片。在整个扫描过程中，借助生命体征监测仪实时监控大鼠的生命体征，以便根据需要调整麻醉深度和扫描参数，确保扫描过程中大鼠的稳定状态。
1.6　神经行为学测试
在ICH 后 1、3及7 d，由对实验信息不知情的3个独立研究人员通过改良神经严重程度评分（modified neurological severity score，mNSS）及啮齿动物转角实验评估各组大鼠ICH后短期神经功能［14］。
1.6.1　神经功能评分
使用改良功能评分方法，该方法能够全面系统的评估动物的神经功能，包括运动功能、感觉功能、反射功能和平衡能力。评分为0~18分，其中0分表示正常神经功能，18分表示最严重的神经功能缺损。各组大鼠的每只动物均进行3次测试，并在测试后计算平均分数。
1.6.2　转角实验
转角实验测试装置由2块板组成，边缘以30° 的角连接，并在连接处留有小缝。实验测试阶段：将大鼠放置在转角测试装置中，观察并记录大鼠接近拐角时的转弯方向。实验数据分析阶段：总共记录10次测试的转弯选择，并计算左转的百分比，进而评估大鼠的不对称感觉运动障碍程度。
1.7　GPX4蛋白Western blot检测与定量分析
在ICH 后第5天，大鼠进行全身深度麻醉（麻醉方法同1.4）后利用4 ℃预冷的PBS进行心脏灌注。脑样本在液氮中快速冷冻后，储存在-80 ℃箱中。如既往研究进行Western blot实验 ［15］。使用 RIPA裂解缓冲液在4 ℃下以3 000 r/min离心30 min，匀浆脑组织样品，通过电泳、转膜及封闭处理后，在4 ℃条件下与一抗（兔抗GPX4，1∶1 000）共同孵育过夜。次日，使用Tris-HCl缓冲盐溶液（TBST）对膜在室温下进行充分洗涤3次，每次5 min。在室温下将膜与二抗（山羊抗兔，1∶1 000）进行孵育2 h，TBST在室温下对膜进行充分洗涤3次，每次5 min。应用ECL Plus化学发光试剂，并借助成像系统进行可视化检测。使用Image J软件进行灰度值的计算。
1.8　多重免疫荧光染色与定量分析
ICH后5 d对大鼠进行全身深度麻醉（麻醉方法同1.4）后，经心脏灌注4 ℃预冷的PBS和4%多聚甲醛。取出大脑，浸入4%多聚甲醛48 h，将脑组织通过石蜡包埋并切成5 μm厚的薄片。通过脱蜡、水化、抗原修复、封闭等处理后，滴加一抗（兔抗CD68，1∶800）4 ℃孵育过夜，第2天在室温下通过PBST浸洗3次，每次5 min，滴加polymer-HRP羊抗兔二抗在室温下孵育30 min，再次PBST浸洗3次，每次5 min，滴加TYR-520荧光染料于室温下孵育10 min。重复上述操作进行抗原修复、封闭处理，滴加一抗（兔抗IBA1，1∶1 000）在4 ℃下孵育过夜后，PBST按同样的方法漂洗后滴加polymer-HRP羊抗兔二抗室温避光孵育30 min，PBST浸洗后滴加TYR-570荧光染料室温避光孵育10 min，PBST同法浸洗后滴加DAPI室温避光孵育10 min，PBST再次洗涤后封片并利用共聚焦显微镜观察获得荧光图像。对实验信息不知情的3个独立研究人员通过在每只大鼠左侧纹状体血肿区域随机选取3~5个区域进行观察，利用Image pro plu6.0软件中count/size功能（基于面积阈值设定的细胞计数参数）对IBA1和CD68阳性细胞进行计数，IBA1和CD68共同表达的阳性细胞作为双阳性细胞计数，对每只大鼠3~5个随机区域的分析结果取平均值。
1.9　RT-qPCR实验
根据制造商的方案，在ICH 后第5天使用RNA提取液提取大鼠ICH周围血肿组织中的总RNA。使用定量PCR专用反转录试剂盒PrimeScript™ RT reagent Kit with gDNA Eraser将RNA反转录成cDNA。使用表1列出的合成引物（中国生工生物工程股份有限公司）和SYBR® Green Realtime PCR Master Mix预混液进行RT-qPCR。在RT-qPCR系统上进行数据收集。以GAPDH为内参，利用阈值循环数对每个基因的相对定量值进行测定 ［16］。
1.10　伊文思蓝染色
采用随机数字表法将 SD 大鼠分为实验组与溶剂对照组，实验组按经腹腔注射10 mg/（kg·d）剂量DA414溶液，对照组注射等体积玉米油溶剂，连续干预5 d。末次给药后，经尾静脉注射2%伊文思蓝溶液（4 mg/kg），30 min后全身麻醉（麻醉方法同1.4）。待麻醉深度达到痛觉反射消失后，经心脏灌注生理盐水快速处死动物，完整摘取脑组织及肝脏。对全脑及肝脏进行大体标本拍照，将脑组织置于脑切片模具中制备连续冠状切片，并进行拍照记录。
1.11　苏木精-伊红染色法（hematoxylin-eosin staining，HE）
在构建ICH模型后的第5天，对大鼠腹腔注射20%乌拉坦麻醉溶液（以0.9%生理盐水配制，7 mL/kg）实施全身麻醉，待大鼠完全失去反应，心脏灌注4 ℃预冷的PBS和4%多聚甲醛。取出心脏、肝脏和肾脏，置于4%多聚甲醛中固定48 h。固定完成后，组织依次经过脱水、石蜡包埋、切片以及酒精梯度水化处理。在玻片上滴加苏木精染色液，染色5 min，用流水冲洗以去除多余的染液，并在显微镜下检查染色效果。将切片置于1%盐酸酒精中进行分化，时间控制在1~3 s，置于自来水中浸泡5~10 min以使切片颜色返蓝，并再次在显微镜下观察颜色变化。接着，滴加0.5%伊红染液，染色10~15 s，用蒸馏水清洗，并在显微镜下观察。通过梯度脱水和二甲苯透明处理后，使用中性树胶进行封片。在显微镜下观察并拍摄图像。
1.12　肝肾功能的测定
各组大鼠麻醉（麻醉方法同1.4）后经眶后静脉丛采血，于 4 ℃条件下以3 000 r/min 离心15 min分离血清，采用全自动生化分析仪检测血清肝功能指标丙氨酸氨基转移酶（alanine transaminase， ALT）、天冬氨酸氨基转移酶（aspartate aminotransferase， AST）、直接胆红素（direct bilirubin，DBIL）、总胆红素（total bilirubin， TBIL）、球蛋白（globulin， GLB）、白蛋白（albumin， ALB）、总蛋白（total protein， TP）及肾功能指标尿素（urea， UREA）、肌酐（creatinine， CREA）及尿酸（uric acid， UA）。
1.13　统计学分析
本研究采用GraphPad Prism 9.3 软件进行统计学分析。采用Shapiro-Wilk检验来评估数据分布的正态性。正态分布的计量资料用x¯±s表示，非正态分布用M（P25，P75）表示。在进行组间比较时，对满足正态分布且方差齐性（通过Bartlett检验验证）的数据，采用单因素方差分析（one-way ANOVA）进行整体组间比较。对非正态分布或方差不齐数据，则采用非参数Kruskal-Wallis H检验进行全局分析，并通过Dunn’s法校正多重比较的显著性水平。P<0.05代表差异具有统计学意义。
2　结果
收起
2.1　DA414 显著改善大鼠脑出血模型的脑损伤体积
血肿体积大小是评估脑出血的重要指标。使用病理组织和 MRI两种检测方法观察血肿体积大小以评估 DA414 在大鼠 ICH 模型中的作用。脑组织灌注后进行切片。血肿体积分析显示，与模型组相比，DA414 干预显著增强血肿吸收（P<0.05，图2A、B）。采用 MRI 的 T2 加权相手动描述和测量脑组织血肿体积。结果表明，与模型组相比，10 mg/（kg·d）DA414组（P<0.01）与5 mg/（kg·d）DA414组（P<0.05）处理后均显著促进ICH 血肿吸收，并减轻脑水肿（图2C、D）。结果提示，DA414治疗可显著促进ICH血肿的吸收，减少脑水肿含量，且在10 mg/（kg·d）剂量下效果更显著。
2.2　DA414 显著改善大鼠脑出血模型神经功能缺损
神经功能评分和啮齿动物转角实验评估ICH后神经功能缺损，结果显示，与假手术组相比，模型组在1、3和7 d均表现出严重的神经功能缺损（P<0.001，图3A）。与模型组相比，ICH后10 mg/（kg·d）DA414组在第3、7天时神经功能显著改善（P<0.05，图3A）；第7天时，与第3天5 mg/（kg·d） DA414组相比，10 mg/（kg·d）DA414组神经功能改善效果更好（P<0.001，图3A）。在啮齿动物转角实验中，大鼠ICH模型构建后第1、3、7天均出现显著的不对称运动（P<0.001，图3B）；与5 mg/（kg·d） DA414组相比，在第3天和第7天时10 mg/（kg·d） DA414组的左转率改善效果更佳（P<0.01，图3B）。结果提示，DA414能明显改善ICH大鼠的神经缺损功能，并且在予以10 mg/（kg·d）时效果最显著，这为后续机制研究提供了最佳剂量选择依据。
2.3　DA414 显著上调大鼠脑出血模型铁死亡关键蛋白GPX4的表达
为了研究DA414对ICH后诱导铁死亡的作用。本研究利用Western blot实验，比较了DA414处理对GPX4蛋白表达的影响。与模型组相比，10 mg/（kg·d） DA414组的处理明显升高GPX4蛋白表达（P<0.01，图4）。结果显示，DA414能够有效升高铁死亡重要因子GPX4的表达，提示铁死亡的抑制可能是DA414治疗ICH的重要疗效因素。
2.4　DA414显著抑制大鼠脑出血模型血肿周围组织中小胶质细胞的活化
小胶质细胞不断监测微环境，并根据大脑环境的变化迅速激活。在模型组，ICH血肿周围组织经历了“阿米巴样”形态学的变化，其主要特征表现为突起变短、变厚、分支变稀疏以及胞体变大（图5A）。与模型组相比，10 mg/（kg·d） DA414组表现为胞体体积减少的特征（图5A）。另外，利用了荧光免疫组化对IBA1与CD68的共定位鉴定了活化的小胶质细胞。结果表明，与模型组相比，10 mg/（kg·d） DA414组显著抑制血肿周围IBA1阳性细胞数量（P<0.01，图5B），同时显著降低CD68阳性细胞的表达（P<0.001，图5C），表明DA414显著抑制ICH后小胶质细胞的募集；进一步研究发现，与模型组相比，10 mg/（kg·d） DA414组减少血肿周围IBA1/CD68双阳性细胞数量（P<0.001，图5D），这表明DA414在ICH后5 d显著减轻小胶质细胞活化。结果提示，DA414抑制小胶质细胞的活化，减轻了ICH后的炎症反应。
2.5　DA414显著上调大鼠脑出血模型的抑炎因子并下调抗炎因子的mRNA水平
炎症反应也是ICH后神经损伤的核心机制之一。RT-qPCR结果显示，与模型组相比，10 mg/（kg·d） DA414组显著下调ICH模型大鼠NLRP3炎症小体通路关键分子（NLRP3、Caspase-1、IL-1β）的mRNA水平（P<0.01，图6A~D）。鉴于炎症细胞因子的释放可调节铁蛋白的合成，从而影响铁在细胞和组织中的储存。因此，进一步检测IL-18、TLR4、IL-6、TNF-α等促炎细胞因子和IL-4和IL-10抑炎细胞因子的表达。结果表明，与模型组相比，10 mg/（kg·d） DA414组显著降低TLR4（P<0.05）、IL-6（P<0.05）、IL-18（P<0.01）、TNF-α（P<0.01）的mRNA表达水平，同时也显著提升了IL-4和IL-10的mRNA表达水平（P<0.05，图6E~I）。综上所述，DA414改善ICH后血肿区域的促炎/抗炎平衡，重塑神经炎症微环境。
2.6　DA414处理对大鼠ICH模型的肝脏、肾脏、心脏组织形态及功能无影响
DA414具有良好的BBB渗透性，为了明确DA414 处理是否影响BBB的完整性，本研究采用伊文思蓝染色，结果显示，DA414 连续处理 5 d并未见明显的伊文思蓝渗漏（图7A）。为了评估 DA414 在体内的安全性，本研究对假手术组、模型组及10 mg/（kg·d） DA414组大鼠的肝脏、肾脏、心脏组织进行HE染色。首次给药 5 d后，结果显示，10 mg/（kg·d） DA414组大鼠的肝细胞排列成索状，肝脏中央静脉和小叶间血管清晰可见；肾小球和肾小管结构清晰，肾间质无明显水肿，无炎症细胞浸润；心脏组织没有明显的胞质空泡化、炎症浸润灶或心肌细胞的坏死等（图7B）。收集以上3 组大鼠血液检测肝肾功能。结果提示，在使用 DA414 处理后，各项指标与假手术组、模型组无明显差别，差异无统计学意义（表2）。结果提示，DA414对大鼠ICH后的肝脏、肾脏、心脏无明显损伤。
3　讨论
收起
3.1　DA414在大鼠ICH模型中展现优越疗效
本研究发现，DA414显著抑制了大鼠ICH模型中血肿周围铁死亡，减轻血肿周围的炎症反应，并促进神经功能的恢复。更重要的是，DA414展现出优越的治疗效果，并在大鼠模型中表现出良好的临床安全性，表明其在改善ICH后神经损伤和促进功能修复方面具有显著的潜力，为ICH的治疗提供了新的方向。本研究揭示DA414通过抑制铁死亡并调控炎症的协同机制改善ICH损伤，其为ICH治疗药物的进一步开发提供了重要科学依据。
3.2　DA414通过抑制GPX4表达阻止大鼠ICH模型中铁死亡
研究表明，ICH损伤后，血肿中的红细胞释放过量的血红蛋白，进而对神经元产生细胞毒性作用，导致细胞膜、蛋白质和DNA等结构的损伤［17］。红细胞中释放的过量铁可能引发芬顿反应，从而诱导铁死亡［18］。铁死亡是一种由铁依赖性脂质过氧化物介导的细胞死亡形式，在ICH后的病理机制中发挥着关键作用［19］。出血发生24 h后，铁开始释放到脑组织中，并且铁死亡水平可持续升高，至少持续28 d［20-21］。越来越多的证据表明，ICH中的铁超载显著加剧了血肿周围水肿、过氧化物积累和细胞死亡［22］。更为重要的是，ICH后脑内铁的积累需要更长时间才能清除，这可能是导致ICH后迟发性神经退行性变、脑萎缩及长期神经功能缺损的部分原因［23］。DA414对ICH的保护作用可能涉及多个机制，其中抑制铁死亡显然是其核心机制之一。GPX4是唯一用于脂质过氧化物还原的酶，在经典的GPX4调控铁死亡机制中，胱氨酸通过胱氨酸/谷氨酸反向转运体进入细胞，接着在谷胱甘肽（glutathione， GSH）或硫氧还蛋白还原酶1依赖的胱氨酸还原途径中还原生成半胱氨酸，促进GSH的生成。GSH是一种强效的还原剂，可作为GPX4的辅因子，将具有细胞毒性的磷脂氢过氧化物（phospholipid hydroperoxide， PLOOHs）还原为 PLOOHs相应的醇，当GSH耗尽或GPX4失活时，脂质过氧化物积累，从而触发铁死亡［24-25］。本研究发现，DA414显著升高大鼠ICH模型中铁死亡重要蛋白GPX4的表达，有效阻止了铁死亡的发生，这可能是其发挥保护作用的关键所在。
3.3　DA414抑制ICH后的炎症反应
炎症反应是ICH后损伤的关键因素之一。ICH后炎症反应的过度激活是导致ICH后继发性神经损伤的重要原因［26-27］。既往研究表明，炎症反应对铁代谢紊乱和氧化还原系统失衡至关重要。例如，IL-1β、IL-6、TNF-α和IFN-γ等促炎细胞因子可调节铁蛋白的合成，从而影响铁在细胞和组织中的储存。而铁死亡具有免疫刺激作用，并促进炎症。反过来，研究表明，炎症反应可介导铁死亡的发生［28］。小胶质细胞作为中枢神经系统的一种独特的免疫细胞，与大脑中炎症性疾病的发病机制密切相关。既往研究提示，小胶质细胞易受铁死亡的影响，激活的小胶质细胞与NLRP3的生成有关，并促进毒性炎症因子释放，从而促进神经元变性死亡［29-30］。本研究表明，DA414显著抑制了小胶质细胞的激活，同时降低了ICH模型中血肿周围炎症小体NLRP3及促炎因子的表达，如TNF-α和IL-6等。这一发现提示，DA414可能通过抑制铁死亡相关的炎症反应，减轻ICH诱导的继发性损伤。尽管本研究初步评估了小胶质细胞参与其中的影响，不排除其他炎症细胞或因子参与其中，仍需要进一步研究炎症与铁死亡之间的相互作用。此外，进一步研究DA414在铁死亡与炎症反应调控中的具体机制，将有助于拓展其在ICH治疗中的应用潜力。
3.4　DA414对ICH治疗有效且安全
在开发ICH治疗药物时，安全性是至关重要的考虑因素。尽管本研究并未探索DA414长期应用可能的毒副作用、后遗效应及成瘾性等，但短期应用于ICH大鼠模型中，DA414未表现出对肝脏、肾脏和心脏等主要器官的明显毒性，为其潜在的临床应用提供了有力支持。实验结果表明，DA414不仅具有良好的治疗效果，还表现出较高的安全性。与此相比，许多现有的铁死亡抑制剂，如Fer-1，虽然在实验研究中显示出一定的治疗效果，但常因药物毒性、BBB穿透能力差、易被氧化及半衰期短等缺点而限制其临床应用。DA414的显著优势在于其良好的BBB穿透能力和低毒性，其半衰期可达20 h，使其成为ICH相关疾病的有力候选药物。其次，与其他吩噻嗪衍生物相比，其化学结构是通过在吩噻嗪的2位（R2）加入苯乙基及苯基环的R4位加入甲基哌嗪，表现出最有效的铁死亡抑制效应及最强活性［9］。然而，本研究的局限性也需要明确。当前的研究中仅进行了两种剂量的探索，未来需要进一步对剂量与给药方式进行全面探索，改善研究结果中可能出现的偏倚。另外，虽然本研究观察到了DA414在短期实验中的有效性，但没有评估其在ICH后的长期影响。未来的研究应重点关注DA414对ICH具体作用机制和其长期脑损伤的保护作用，以及其可能的副作用或毒性反应。
综上所述，本研究发现DA414通过抑制铁死亡和减轻炎症，显著改善了ICH模型中的神经损伤和功能恢复，为DA414作为ICH治疗药物的潜力提供了有力支持。未来的研究应聚焦于揭示其抑制铁死亡的具体作用机制，并评估其在长期治疗中的效果与安全性。研究表明，针对铁死亡的干预可能是治疗ICH引起脑损伤的有效策略，为临床提供了新的治疗方向。同时，DA414的临床安全性和有效性值得进一步验证。

文献
收起
参考文献 引证文献
排序方式：
1
SHETH K N. Spontaneous intracerebral hemorrhage［J］. N Engl J Med，2022，387（17）：1589-1596.
2
MURTHY S B，ZHANG C N，DIAZ I，et al. Association between intracerebral hemorrhage and subsequent arterial ischemic events in participants from 4 population-based cohort studies［J］. JAMA Neurol，2021，78（7）：809-816.
3
DUPRÉ N，DRIEU A，JOUTEL A. Pathophysiology of cerebral small vessel disease：a journey through recent discoveries［J］. J Clin Invest，2024，134（10）：e172841.
4
SUN Y Y，LI Q，GUO H X，et al. Ferroptosis and iron metabolism after intracerebral hemorrhage［J］. Cells，2022，12（1）：90.
5
LI J，CAO F，YIN H L，et al. Ferroptosis：past，present and future ［J］. Cell Death Disease，2020，11（2）：88.
6
CHEN J H，WANG Y H，WU J Y，et al. The potential value of targeting ferroptosis in early brain injury after acute CNS disease［J］. Front Mol Neurosci，2020，13：110.
7
DIXON S J，LEMBERG K M，LAMPRECHT M R，et al. Ferroptosis：an iron-dependent form of nonapoptotic cell death［J］. Cell，2012，149（5）：1060-1072.
8
SHAH R，MARGISON K，PRATT D A. The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death［J］. ACS Chem Biol，2017，12（10）：2538-2545.
9
WEI Y F，SONG X X，GAO Y，et al. Iron toxicity in intracerebral hemorrhage：physiopathological and therapeutic implications［J］. Brain Res Bull，2022，178：144-154.
10
YANG W，LIU X L，SONG C L，et al. Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model［J］. Eur J Med Chem，2021，209：112842.
11
YAN J，ZUO G，SHERCHAN P，et al. CCR1 activation promotes neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after intracerebral hemorrhage in mice［J］. Neurotherapeutics，2020，17（3）：1170-1183.
12
CHEN R，XIE Q，XIE L X，et al. Thioredoxin1 binding metastasis-associated lung adenocarcinoma transcript 1 attenuates inflammation and apoptosis after intracerebral hemorrhage［J］. Aging Dis，2024，15（3）：1384-1397.
13
ZIMNY A，NESKA-MATUSZEWSKA M，BLADOWSKA J，et al. Intracranial lesions with low signal intensity on T2-weighted MR images—review of pathologies ［J］. Pol J Radiol，2015，80：40-50.
14
REN H L，PAN Y，WANG D N，et al. CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage［J］. Pharmacol Res，2023，196：106912.
15
CHEN S P，ZHAO L H，SHERCHAN P，et al. Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice［J］. J Neuroinflamm，2018，15（1）：106.
16
SCHMITTGEN T D，LIVAK K J. Analyzing real-time PCR data by the comparative CT method［J］. Nat Protoc，2008，3：1101-1108.
17
ZHANG X Y，ZHANG Y，SU Q Y，et al. Ion channel dysregulation following intracerebral hemorrhage［J］. Neurosci Bull，2024，40（3）：401-414.
18
TANG D L，CHEN X，KANG R，et al. Ferroptosis：molecular mechanisms and health implications［J］. Cell Res，2021，31（2）：107-125.
19
WANG Y M，WU S，LI Q，et al. Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes［J］. Adv Sci，2023，10（24）：e2300325.
20
CHENG Y J，ZHANG Z Q，TANG H，et al. Mitochondrial inhibitor rotenone triggers and enhances neuronal ferroptosis following intracerebral hemorrhage［J］. ACS Chem Neurosci，2023，14（6）：1071-1079.
21
ZILLE M，KARUPPAGOUNDER S S，CHEN Y X，et al. Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis［J］. Stroke，2017，48（4）：1033-1043.
22
WAN J R，REN H L，WANG J. Iron toxicity，lipid peroxidation and ferroptosis after intracerebral haemorrhage［J］. Stroke Vasc Neurol，2019，4（2）：93-95.
23
SUN K Y，BAI X Y，ZHANG L，et al. A new strategy for the treatment of intracerebral hemorrhage：ferroptosis［J］. Exp Neurol，2024，382：114961.
24
DIXON S J，OLZMANN J A. The cell biology of ferroptosis［J］. Nat Rev Mol Cell Biol，2024，25：424-442.
25
JIANG X J，STOCKWELL B R，CONRAD M. Ferroptosis：mechanisms，biology and role in disease［J］. Nat Rev Mol Cell Biol，2021，22（4）：266-282.
26
SHI K B，TIAN D C，LI Z G，et al. Global brain inflammation in stroke［J］. Lancet Neurol，2019，18（11）：1058-1066.
27
张忠意，唐于广，代金雨，等. G蛋白偶联受体39在小鼠脑出血后脑损伤的作用及机制研究［J］. 陆军军医大学学报，2024，46（11）：1254-1264.
ZHANG Z Y，TANG Y G，DAI J Y，et al. Role and mechanisms of G-protein-coupled receptor 39 in brain injury after intracerebral hemorrhage in mice［J］. J Amry Med Univ，2024，46（11）：1254-1264.
28
CHEN Y，FANG Z M，YI X，et al. The interaction between ferroptosis and inflammatory signaling pathways［J］. Cell Death Dis，2023，14（3）：205.
29
WANG Y，LIU Z H，LI L Y，et al. Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke［J］. J Nanobiotechnology，2024，22（1）：291.
30
YOON S H，KIM C Y，LEE E，et al. Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice［J］. Nat Commun，2025，16（1）：699.
2025年第47卷第9期
PDF下载
18
7
引用本文
BibTeX
文章信息
doi: 10.16016/j.2097-0927.202501047
  • 接收时间：2025-01-16
  • 首发时间：2026-10-28
  • 出版时间：2025-05-15
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2025-01-16
  • 修回日期：2025-02-17
基金
作者信息
    1陆军军医大学（第三军医大学）第二附属医院神经内科，重庆

通讯作者:

杨清武，E-mail：
YANG Qingwu，E-mail：
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/ljjydxxb/CN/10.16016/j.2097-0927.202501047
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62662699（运营及技术支持）
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持