Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury
BackgroundCerebral ischemia-reperfusion injury (CIRI) is a secondary brain injury that occurs after thrombolysis and is a primary cause of death in ischemic stroke patients. Antioxidants that effectively reduce oxidative stress are an efficient treatment approach for CIRI. Here, a novel diimide comp...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1552717/full |
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| author | Lili Huang Yinqi Chen Hua Zhou Huihui Chen Xiping Wu Zhuochao Wu Zhoudi Liu Zhiwei Zheng |
| author_facet | Lili Huang Yinqi Chen Hua Zhou Huihui Chen Xiping Wu Zhuochao Wu Zhoudi Liu Zhiwei Zheng |
| author_sort | Lili Huang |
| collection | DOAJ |
| description | BackgroundCerebral ischemia-reperfusion injury (CIRI) is a secondary brain injury that occurs after thrombolysis and is a primary cause of death in ischemic stroke patients. Antioxidants that effectively reduce oxidative stress are an efficient treatment approach for CIRI. Here, a novel diimide compound was synthesized using the chemical structure of previously designed anti-inflammatory skeletons.Methods and resultsThe antioxidant activities of five compounds (Z1–Z5) were preliminarily evaluated using the hydrogen peroxide-induced PC12 cell damage model, of which Z3 exhibited the best antioxidant effect, even exceeding that of the positive control (tert-butylhydroquinone). Enrichment analysis using network targeting and network pharmacology methods predicted seven candidate core target genes of Z3 in CIRI. Of these targets, computer molecular docking analysis predicted that Z3 has the strongest binding affinity for nuclear factor erythroid 2-related factor (Nrf2). MTT and colony formation assays, reactive oxygen species analysis, immunofluorescence, and immunoblotting experiments verified that Z3 reduced reactive oxygen species to play a protective antioxidant role via the Nrf2/hemoxygenase 1 (HO-1) pathway. The protective effect of Z3 in vivo was explored through TTC staining and neurobehavioral scoring of CIRI model mice.ConclusionThis study provides a new drug development strategy and candidate drug for the treatment of CIRI, offering ideas for the design of new antioxidants. |
| format | Article |
| id | doaj-art-e471478420f04eeca9ea8723bebb0b50 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-e471478420f04eeca9ea8723bebb0b502025-08-20T01:55:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15527171552717Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injuryLili Huang0Yinqi Chen1Hua Zhou2Huihui Chen3Xiping Wu4Zhuochao Wu5Zhoudi Liu6Zhiwei Zheng7Lihuili Hospital Affiliated to Ningbo University, Ningbo, ChinaShaoxing Second Hospital, Shaoxing, ChinaLihuili Hospital Affiliated to Ningbo University, Ningbo, ChinaLihuili Hospital Affiliated to Ningbo University, Ningbo, ChinaLihuili Hospital Affiliated to Ningbo University, Ningbo, ChinaLihuili Hospital Affiliated to Ningbo University, Ningbo, ChinaDepartment of Pharmacy, Shaoxing People’s Hospital, Shaoxing, ChinaZhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, ChinaBackgroundCerebral ischemia-reperfusion injury (CIRI) is a secondary brain injury that occurs after thrombolysis and is a primary cause of death in ischemic stroke patients. Antioxidants that effectively reduce oxidative stress are an efficient treatment approach for CIRI. Here, a novel diimide compound was synthesized using the chemical structure of previously designed anti-inflammatory skeletons.Methods and resultsThe antioxidant activities of five compounds (Z1–Z5) were preliminarily evaluated using the hydrogen peroxide-induced PC12 cell damage model, of which Z3 exhibited the best antioxidant effect, even exceeding that of the positive control (tert-butylhydroquinone). Enrichment analysis using network targeting and network pharmacology methods predicted seven candidate core target genes of Z3 in CIRI. Of these targets, computer molecular docking analysis predicted that Z3 has the strongest binding affinity for nuclear factor erythroid 2-related factor (Nrf2). MTT and colony formation assays, reactive oxygen species analysis, immunofluorescence, and immunoblotting experiments verified that Z3 reduced reactive oxygen species to play a protective antioxidant role via the Nrf2/hemoxygenase 1 (HO-1) pathway. The protective effect of Z3 in vivo was explored through TTC staining and neurobehavioral scoring of CIRI model mice.ConclusionThis study provides a new drug development strategy and candidate drug for the treatment of CIRI, offering ideas for the design of new antioxidants.https://www.frontiersin.org/articles/10.3389/fphar.2025.1552717/fullcerebral ischemia-reperfusion injuryoxidative stressantioxidantnetwork pharmacologymolecular dockingNrf2 signaling pathway |
| spellingShingle | Lili Huang Yinqi Chen Hua Zhou Huihui Chen Xiping Wu Zhuochao Wu Zhoudi Liu Zhiwei Zheng Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury Frontiers in Pharmacology cerebral ischemia-reperfusion injury oxidative stress antioxidant network pharmacology molecular docking Nrf2 signaling pathway |
| title | Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury |
| title_full | Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury |
| title_fullStr | Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury |
| title_full_unstemmed | Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury |
| title_short | Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury |
| title_sort | synthesis target analysis and cerebroprotective effects of novel imide antioxidants via the nrf2 ho 1 pathway in cerebral ischemia reperfusion injury |
| topic | cerebral ischemia-reperfusion injury oxidative stress antioxidant network pharmacology molecular docking Nrf2 signaling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1552717/full |
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