Esketamine Suppresses Astrocyte-Driven Neuroinflammation in Traumatic Brain Injury via the METTL5/c-Myc/PD-L1
Lan Luo, Miao Yu, Xiaodong Li, Yonghong Bi, Pengyu Duan, Yao Meng, Zhehao Jin, Weiyu Feng, Longfei Li, Yuling Xing, Jiali Chen, Bing Zhang
Neurochemical Research March 13, 2026 DOI: 10.1007/s11064-026-04724-8 via OpenAlex
Summary
AI-generated from the abstractEsketamine given to mice after traumatic brain injury (TBI) improved neurological outcomes, reduced neuronal death, and lessened neuroinflammation. The drug suppressed astrocyte activation, inhibited pro-inflammatory A1 astrocyte differentiation, and promoted protective A2 astrocyte formation. These effects occurred through inhibition of the METTL5/c-Myc/PD-L1 signaling pathway. The findings suggest esketamine has significant anti-inflammatory and neuroprotective properties that could be relevant for treating TBI.
Study at a glance
| Characteristics | Animal study with in vitro experiments Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Esketamine |
| Duration | 7 consecutive days starting 2 hours post-injury |
| Keywords | Neuroinflammation Astrocyte Traumatic brain injury Neuroprotection Neurology |
| Key finding | Esketamine alleviates neuroinflammation and promotes neuroprotection after TBI by inhibiting astrocyte activation and shifting polarization toward A2 astrocytes via the METTL5/c-Myc/PD-L1 pathway. |
Abstract
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.