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Icariside Ⅱ preconditioning evokes robust neuroprotection against ischemic stroke: Targeting Nrf2 mediated by OXPHOS/NF-κB/ferroptosis pathway
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  • Jianmei Gao,
  • Congjian Ma,
  • Nana Chen,
  • Jianyong Zhang,
  • Fan Xu,
  • Fei Li,
  • Yuqi He,
  • Qihai Gong
Jianmei Gao
Zunyi Medical University

Corresponding Author:[email protected]

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Congjian Ma
Zunyi Medical University
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Nana Chen
Zunyi Medical University
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Jianyong Zhang
Zunyi Medical University
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Fan Xu
Zunyi Medical University
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Fei Li
Zunyi Medical University
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Yuqi He
Zunyi Medical University
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Qihai Gong
Zunyi Medical University
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Background and Purpose: Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischemic preconditioning (IPC). Icariside Ⅱ (ICS Ⅱ) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify whether ICS Ⅱ simulates IPC neuroprotection and to decipher if the astrocytic-Nrf2 is contributed to ICS Ⅱ preconditioning against ischemic stroke. Experimental Approach: Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia and oxygen-glucose deprivation (OGD)-injured primary astrocytes were used to explore the neuroprotective of ICS Ⅱ preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS Ⅱ to determine whether ICS Ⅱ exerts its neuroprotection by activating Nrf2. Key results: ICS Ⅱ pre-treatment dramatically mitigated the cerebral injury in ischemic stroke mice along with restoring long-term recovery. Furthermore, proteomics screening identified Nrf2 is a crucial gene evoked by ICS Ⅱ stimulation and is required for the anti-oxidative effect and anti-inflammatory effect of ICS Ⅱ. Most interestingly, ICS Ⅱ directly bound with Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS Ⅱ pre-treatment exerted cytoprotective effect on astrocytes after lethal oxygen-glucose deprivation insult via promoting Nrf2 nuclear translocation and mediating OXPHOS/NF-κB/ferroptosis axis. While, abrogated neuroprotection in Nrf2-deficient mice and astrocyte potently supports Nrf2-dependent neuroprotection of ICS Ⅱ. Conclusions and implications: ICS Ⅱ preconditioning confers robust neuroprotection against ischemic stroke via astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis, it is concluded that ICS Ⅱ will be serve as a promising Nrf2 activator to rescue ischemic stroke.
20 Mar 2022Submitted to British Journal of Pharmacology
21 Mar 2022Submission Checks Completed
21 Mar 2022Assigned to Editor
31 Mar 2022Reviewer(s) Assigned
12 May 2022Review(s) Completed, Editorial Evaluation Pending
28 May 2022Editorial Decision: Revise Minor
10 Jul 20221st Revision Received
12 Jul 2022Submission Checks Completed
12 Jul 2022Assigned to Editor
20 Jul 2022Reviewer(s) Assigned
11 Aug 2022Review(s) Completed, Editorial Evaluation Pending
13 Aug 2022Editorial Decision: Revise Minor
28 Aug 20222nd Revision Received
29 Aug 2022Submission Checks Completed
29 Aug 2022Assigned to Editor
30 Aug 2022Editorial Decision: Accept