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<p>Traumatic brain injury (TBI) is a major global health issue leading to high mortality and disability. Activated astrocytes are one of the pivotal driving factors in the neuroinflammatory cascade following TBI. This study aims to investigate the role of esketamine on TBI and the underlying mechanism. Mice received a mouse weight-drop cortical impact or sham surgery and TBI mice were treated with either vehicle or esketamine at 2&#xa0;h post-injury for 7 consecutive days. The modified Neurological Severity Scoring system, Rotarod test, Open Field test and Novel Object Recognition test were used to assess the neurological function after TBI. And cortical tissues surrounding focal trauma were obtained for Nissl staining, immunofluorescence, ELISA assay and western blotting. In vitro, astrocytes were induced with LPS, followed by the addition of esketamine to the culture medium. After a 24&#xa0;h exposure, the astrocytes were collected for CCK-8 assay, qRT-PCR, western blotting, immunofluorescence and Co-IP analysis. Esketamine dramatically improved the neurological outcome of mice and reduced neuronal cell death (<i>P</i> &lt; 0.05) and neuroinflammation after TBI. Its anti-inflammatory benefits stem from its ability to suppress astrocyte activation (<i>P</i> &lt; 0.05), inhibit pro-inflammatory A1 astrocyte differentiation (<i>P</i> &lt; 0.01), and promote the formation of protective A2 astrocytes (<i>P</i> &lt; 0.01). Esketamine exerts its effects by inhibiting the METTL5/c-Myc/PD-L1 signaling pathway. Esketamine can effectively alleviate activated astrocytes and promote the polarization of activated astrocytes toward A2 following TBI by inhibiting the METTL5/c-Myc/PD-L1, demonstrating significant anti-inflammatory and neuroprotective effects.</p> Graphical Abstract <p></p>

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Esketamine Suppresses Astrocyte-Driven Neuroinflammation in Traumatic Brain Injury via the METTL5/c-Myc/PD-L1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Lan Luo,
  • Miao Yu,
  • Xiaoyan Li,
  • Yonghong Bi,
  • Pengyu Duan,
  • Yao Meng,
  • Zhehao Jin,
  • Weiyu Feng,
  • Longfei Li,
  • Yuling Xing,
  • Jiali Chen,
  • Bing Zhang

摘要

Traumatic brain injury (TBI) is a major global health issue leading to high mortality and disability. Activated astrocytes are one of the pivotal driving factors in the neuroinflammatory cascade following TBI. This study aims to investigate the role of esketamine on TBI and the underlying mechanism. Mice received a mouse weight-drop cortical impact or sham surgery and TBI mice were treated with either vehicle or esketamine at 2 h post-injury for 7 consecutive days. The modified Neurological Severity Scoring system, Rotarod test, Open Field test and Novel Object Recognition test were used to assess the neurological function after TBI. And cortical tissues surrounding focal trauma were obtained for Nissl staining, immunofluorescence, ELISA assay and western blotting. In vitro, astrocytes were induced with LPS, followed by the addition of esketamine to the culture medium. After a 24 h exposure, the astrocytes were collected for CCK-8 assay, qRT-PCR, western blotting, immunofluorescence and Co-IP analysis. Esketamine dramatically improved the neurological outcome of mice and reduced neuronal cell death (P < 0.05) and neuroinflammation after TBI. Its anti-inflammatory benefits stem from its ability to suppress astrocyte activation (P < 0.05), inhibit pro-inflammatory A1 astrocyte differentiation (P < 0.01), and promote the formation of protective A2 astrocytes (P < 0.01). Esketamine exerts its effects by inhibiting the METTL5/c-Myc/PD-L1 signaling pathway. Esketamine can effectively alleviate activated astrocytes and promote the polarization of activated astrocytes toward A2 following TBI by inhibiting the METTL5/c-Myc/PD-L1, demonstrating significant anti-inflammatory and neuroprotective effects.

Graphical Abstract