Esketamine Suppresses Astrocyte-Driven Neuroinflammation in Traumatic Brain Injury via the METTL5/c-Myc/PD-L1
Neurochemical Research – March 13, 2026
Source: OpenAlex
Summary
Esketamine significantly enhances neurological recovery after traumatic brain injury (TBI) by reducing neuroinflammation and neuronal cell death. In a study with mice, treatment initiated two hours post-injury led to improved scores in neurological assessments, with a notable decrease in activated astrocytes. Specifically, esketamine inhibited the harmful A1 astrocyte differentiation by 50% while promoting protective A2 astrocytes by 40%. This effect is mediated through the METTL5/c-Myc/PD-L1 signaling pathway, highlighting its potential in neurology and internal medicine for TBI management.
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.