{"title":"塞拉斯托尔通过抑制神经元铁凋亡和阻断血脑屏障破坏减轻脑出血后的继发性脑损伤","authors":"","doi":"10.1016/j.ibneur.2024.08.003","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage.</p></div><div><h3>Methods</h3><p>We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH).</p></div><div><h3>Results</h3><p>Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites.</p></div><div><h3>Conclusions</h3><p>Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.</p></div>","PeriodicalId":13195,"journal":{"name":"IBRO Neuroscience Reports","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667242124000733/pdfft?md5=b58b04cfa9e8270a4cdf5448f845e38f&pid=1-s2.0-S2667242124000733-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Celastrol alleviates secondary brain injury following intracerebral haemorrhage by inhibiting neuronal ferroptosis and blocking blood-brain barrier disruption\",\"authors\":\"\",\"doi\":\"10.1016/j.ibneur.2024.08.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage.</p></div><div><h3>Methods</h3><p>We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH).</p></div><div><h3>Results</h3><p>Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites.</p></div><div><h3>Conclusions</h3><p>Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.</p></div>\",\"PeriodicalId\":13195,\"journal\":{\"name\":\"IBRO Neuroscience Reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2024-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2667242124000733/pdfft?md5=b58b04cfa9e8270a4cdf5448f845e38f&pid=1-s2.0-S2667242124000733-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"IBRO Neuroscience Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2667242124000733\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"IBRO Neuroscience Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2667242124000733","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
背景随着近年来研究的进展，越来越多的证据表明，青霉烯醇对一系列神经系统疾病具有治疗作用。方法我们利用 ACSL4 过表达载体建立了大鼠脑内出血和肾上腺嗜铬细胞瘤细胞（PC12）OxyHb 模型。使用相应的检测试剂盒评估了铁氧化相关指数，并使用免疫荧光和流式细胞术测量了活性氧（ROS）水平。此外，还进行了定量 PCR（qPCR）和 Western 印迹分析，以评估关键蛋白的表达，并阐明塞拉斯托在脑内出血（ICH）中的作用。此外，对铁氧化相关标记物（如 Fe2+、ROS、MDA 和 SOD）的后续分析表明，仙鹤草醇对 ICH 大鼠和细胞中铁氧化引起的氧化损伤具有保护作用。此外，Western 印迹分析表明，在体外和体内，仙鹤草醇通过调节关键蛋白的表达水平，包括酰基-CoA 合成酶长链家族成员 4（ACSL4）、谷胱甘肽过氧化物酶 4（GPX4）、铁蛋白重链 1（FTH1）和抗转铁蛋白受体 1（TFR1），减轻了铁蛋白沉积。ACSL4的过表达削弱了青蒿素对体外ICH的神经保护作用。分子对接分析表明，西司醇通过 GLU107、GLN109、ASN111 和 LYS357 结合位点与 ACSL4 相互作用。因此，这种药物是治疗 ICH 的一种有前途的候选药物。
Celastrol alleviates secondary brain injury following intracerebral haemorrhage by inhibiting neuronal ferroptosis and blocking blood-brain barrier disruption
Background
Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage.
Methods
We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH).
Results
Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites.
Conclusions
Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.
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