摘要
背景：创伤性脑损伤（TBI）后的继发性损伤包括神经炎症、免疫细胞浸润和代谢失调，从而导致进行性神经损伤。本研究评估了 NMDA 受体拮抗剂艾司卡胺在 TBI 小鼠模型中调节免疫反应、抑制糖酵解和减轻继发性脑损伤的潜力：方法：对雄性 C57BL/6J 小鼠的大脑皮层进行控制性撞击，诱发 TBI。小鼠单独或与 STAT3 激活剂可乐定或糖酵解抑制剂 2-脱氧葡萄糖（2-DG）联合使用艾司卡胺治疗。使用免疫组化、流式细胞术、定量 PCR 和酶联免疫吸附试验（ELISA）对神经功能、BBB 通透性、免疫细胞浸润、巨噬细胞极化和糖酵解活性进行了评估：结果：艾司卡胺治疗能明显减轻脑组织结构损伤，包括挫伤、组织缺失和水肿，同时还能改善创伤性脑损伤小鼠的神经功能。从机理上讲，艾司卡胺在体内和体外都能抑制 CD4 + T 细胞的活化并抑制 Th17 的分化。它还能促进巨噬细胞从促炎的 M1 表型向抗炎的 M2 表型转变。进一步的分析表明，艾司卡胺阻断了 STAT3 的活化，进而减少了对 Th17 细胞增殖和 M1 极化至关重要的糖酵解基因（如 Hk2、Pgk1、Aldoa）的表达。与考来烯胺同时处理可逆转艾司卡胺对STAT3介导的糖酵解的影响，而2-DG则增强了艾司卡胺的抗炎作用：结论：艾司卡胺通过抑制STAT3介导的糖酵解，从而降低Th17和M1巨噬细胞的活性，促进调节性和修复性免疫反应，从而减轻创伤性脑损伤引起的神经炎症和组织损伤。这些发现凸显了艾司卡胺作为创伤性脑损伤治疗选择的潜力，它同时针对免疫调节和代谢途径来减轻继发性损伤。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.
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