Esketamine attenuates traumatic brain injury by modulating STAT3-mediated Glycolysis and immune responses

Abstract

Background: Secondary injury following traumatic brain injury (TBI) involves neuroinflammation, immune cell infiltration, and metabolic dysregulation, leading to progressive neurological damage. This study evaluates the potential of esketamine, an NMDA receptor antagonist, to modulate immune responses, inhibit glycolysis, and mitigate secondary brain injury in a TBI mouse model. Methods: Male C57BL/6J mice were subjected to controlled cortical impact to induce TBI. Mice were treated with esketamine, either alone or combined with the STAT3 activator colivelin, or the glycolysis inhibitor 2-deoxyglucose (2-DG). Neurological function, BBB permeability, immune cell infiltration, macrophage polarization, and glycolytic activity were assessed using immunohistochemistry, flow cytometry, quantitative PCR, and enzyme-linked immunosorbent assay (ELISA). Results: Esketamine treatment significantly reduced structural brain tissue damage, including contusions, tissue loss, and edema, while also improving neurological outcomes in TBI mice. Mechanistically, esketamine inhibited CD4 + T cell activation and suppressed Th17 differentiation both in vivo and in vitro. It also promoted a shift in macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Further analysis revealed that esketamine blocked STAT3 activation, which in turn reduced the expression of glycolytic genes (e.g., Hk2, Pgk1, Aldoa) essential for Th17 cell proliferation and M1 polarization. Co-treatment with colivelin reversed esketamine’s effects on STAT3-mediated glycolysis, while 2-DG enhanced its anti-inflammatory actions. Conclusion: Esketamine attenuates TBI-induced neuroinflammation and tissue damage by inhibiting STAT3-mediated glycolysis, thus reducing Th17 and M1 macrophage activity and promoting regulatory and reparative immune responses. These findings highlight esketamine’s potential as a therapeutic option for TBI, targeting both immune modulation and metabolic pathways to alleviate secondary injury. Clinical trial number: not applicable.