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N-myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury

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A Correction to this article was published on 18 June 2022

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Abstract  

Growing evidence indicates that estrogen plays a pivotal role in neuroprotection against cerebral ischemia, but the molecular mechanism of this protection is still elusive. N‐myc downstream‐regulated gene 2 (Ndrg2), an estrogen-targeted gene, has been shown to exert neuroprotective effects against cerebral ischemia in male mice. However, the role of Ndrg2 in the neuroprotective effect of estrogen remains unknown. In this study, we first detected NDRG2 expression levels in the cortex and striatum in both female and male mice with western blot analyses. We then detected cerebral ischemic injury by constructing middle cerebral artery occlusion and reperfusion (MCAO-R) models in Ndrg2 knockout or conditional knockdown female mice. We further implemented estrogen, ERα, or ERβ agonist replacement in the ovariectomized (OVX) Ndrg2 knockout or conditional knockdown female mice, then tested for NDRG2 expression, glial fibrillary acidic protein (GFAP) expression, and extent of cerebral ischemic injury. We found that NDRG2 expression was significantly higher in female than in male mice in both the cortex and striatum. Ndrg2 knockouts and conditional knockdowns showed significantly aggravated cerebral ischemic injury in female mice. Estrogen and ERβ replacement treatment (DPN) led to NDRG2 upregulation in both the cortex and striatum of OVX mice. Estrogen and DPN also led to GFAP upregulation in OVX mice. However, the effect of estrogen and DPN in activating astrocytes was lost in Ndrg2 knockout OVX mice and primary cultured astrocytes, but partially retained in conditional knockdown OVX mice. Most importantly, we found that the neuroprotective effects of E2 and DPN against cerebral ischemic injury were lost in Ndrg2 knockout OVX mice but partially retained in conditional knockdown OVX mice. These findings demonstrate that estrogen alleviated cerebral ischemic injury via ERβ upregulation of Ndrg2, which could activate astrocytes, indicating that Ndrg2 is a critical mediator of E2-induced neuroprotection against cerebral ischemic injury.

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Data Availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

This work was supported by the National Natural Science Foundation of China (no. 81801138, 81971226, 82003321, 82171464, 82101427, 81901097), Science Key Program of Military Logistics (BLB20J002), National Key Research and Development Program of China (no. 2018YFC2001905).

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Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Military Medical University, Xi’an, 710032, China

    Jin Wang & Wugang Hou

  2. Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China

    Min Liu

  3. Department of Anesthesiology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China

    Min Hou, Miao Sun, Huikai Yang, Xiaoying Zhang, Yanhong Liu & Yulong Ma

  4. Department of Burn and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China

    Lixia Zhang

  5. Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Siyuan Liu

  6. Department of Anesthesiology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, China

    Hang Guo

  7. Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China

    Fei Xie

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  1. Jin Wang
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Contributions

YHL and YLM designed this study and edited the manuscript. JW, ML, and WGH conducted most of the experiments and drafted the manuscript. MH, LXZ, MS, SYL, and FX contributed to the statistical analysis and manuscript editing. HKY, HG, and XYZ contributed to data interpretation. All authors have read and approved the final manuscript.

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Correspondence to Yanhong Liu or Yulong Ma.

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Jin Wang, Min Liu and Wugang Hou in the author list of this article are co-first authors.

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Wang, J., Liu, M., Hou, W. et al. N-myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury. Mol Neurobiol 59, 4793–4804 (2022). https://doi.org/10.1007/s12035-022-02877-5

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