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Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses

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Abstract

Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide. Neuroinflammation involving microglia and astrocyte activation has been demonstrated to play critical role in the secondary injury induced by TBI. A1 astrocytes, which are induced by activated microglia, can directly kill neurons by secreting neurotoxic complement C3. Estrogen has been proved to possess neuroprotective effects, but the effect and underlying mechanism of estrogen on TBI-induced neuroinflammatory injury remain largely unclear. In this study, we constructed an adult male mouse model of TBI and immediately after injury treated the mice with 17β-estradiol (E2) (100 μg/kg, once every day via intraperitoneal injection) for 3 days. We found that E2 treatment significantly alleviated TBI-induced neurological deficits, neuronal injuries, and brain edema and significantly inhibited Iba1 and GFAP expression, which are markers of microglia and astrocyte activation, respectively. E2 treatment also significantly inhibited TLR4 and NF-κB protein expression, and significantly reduced the expression of the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, E2 treatment significantly decreased the number of complement C3d/GFAP-positive cells and complement C3d protein expression. Taking these results together, we concluded that E2 treatment dramatically alleviates TBI neuroinflammatory injury by inhibiting TLR4/NF-κB pathway-mediated microglia and astrocyte activation and neuroinflammation and reducing A1-phenotype neurotoxic astrocyte activation. Our findings indicate that E2 treatment may be a potential therapy strategy for TBI-induced neuroinflammation injury.

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Funding

This work was supported by the National Natural Science Foundation of China (no.81801138, 81971226, 81771411), Key R & D projects in Shaanxi Province (no.2017ZDXMSF059), Defense Science and Technology project (no. 2019-JCJQ-JJ-089), The Beijing Natural Science Foundation (no.7194321).

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Author notes

  1. Jin Wang, Yushu Hou and Lixia Zhang contributed equally to this work.

Authors and Affiliations

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

    Jin Wang, Jianshuai Zhao, Zhen Zhang & Wugang Hou

  2. Department of Anesthesiology, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, 710001, China

    Yushu Hou

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

    Lixia Zhang

  4. Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, China

    Min Liu & Yulong Ma

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  1. Jin Wang
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Correspondence to Yulong Ma or Wugang Hou.

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Wang, J., Hou, Y., Zhang, L. et al. Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses. Mol Neurobiol 58, 1052–1061 (2021). https://doi.org/10.1007/s12035-020-02171-2

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  • DOI: https://doi.org/10.1007/s12035-020-02171-2

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