Zhou Zi-Heng, Chen Xiao-Xiang, Zhang Wen, Shu Bin, Chen Ying
Department of Burn, Wound Repair and Reconstruction, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Pharmacol. 2025 Jul 28;16:1647329. doi: 10.3389/fphar.2025.1647329. eCollection 2025.
Sevoflurane is widely used in pediatric anesthesia and has raised concerns for years regarding its neurotoxic effects on the developing brain. Studies have shown that sevoflurane can lead to neuronal cell death and neuroinflammation, which further contribute to sevoflurane-induced neurotoxicity manifested as delirium or cognitive deficits. However, the molecular mechanism remains poorly understood. A factor of interest is Sin3A-associated protein 130 (SAP130), which can be released by dead or damaged cells and trigger sterile inflammation, exacerbating tissue damage by activating the macrophage-inducible C-type lectin (Mincle) receptor. However, whether the SAP130/Mincle axis is involved in sevoflurane-induced neurotoxicity remains unknown.
Using a young murine sevoflurane exposure model and a primary neuron-microglia co-culture system, we examined changes in neuronal cell death, microglial activation, cytokine production, and the expression levels of SAP130- and Mincle-signaling-associated proteins after sevoflurane exposure. We then applied SAP130-neutralizing antibody and the Syk inhibitor piceatannol to assess the impact of inhibiting the Mincle pathway on microglial activation and sevoflurane-induced neurotoxicity.
The results demonstrated that sevoflurane exposure increased the number of dead neurons with SAP130 upregulation and induced microglial activation with cytokine production in the hippocampus. These changes occurred only in the neuron-microglia co-culture system but not in neuron or microglia monoculture. Neutralizing SAP130 or pharmacologically inhibiting syk diminished microglial activation and neuronal cell death by suppressing the SAP130/Mincle signaling pathway.
These findings suggest that the SAP130/Mincle axis plays a crucial role in neuronal death and microglial activation in sevoflurane-induced neurotoxicity. Targeting this axis emerges as a potential therapeutic strategy to mitigate the neurotoxic effects of sevoflurane.
七氟醚广泛应用于小儿麻醉，多年来一直有人担心其对发育中大脑的神经毒性作用。研究表明，七氟醚可导致神经元细胞死亡和神经炎症，这进一步促成了七氟醚诱导的神经毒性，表现为谵妄或认知缺陷。然而，其分子机制仍知之甚少。一个值得关注的因素是Sin3A相关蛋白130（SAP130），它可由死亡或受损细胞释放，并引发无菌性炎症，通过激活巨噬细胞诱导C型凝集素（Mincle）受体加剧组织损伤。然而，SAP130/Mincle轴是否参与七氟醚诱导的神经毒性尚不清楚。
利用幼鼠七氟醚暴露模型和原代神经元-小胶质细胞共培养系统，我们检测了七氟醚暴露后神经元细胞死亡、小胶质细胞活化、细胞因子产生以及SAP130和Mincle信号相关蛋白表达水平的变化。然后，我们应用SAP130中和抗体和Syk抑制剂白皮杉醇来评估抑制Mincle途径对小胶质细胞活化和七氟醚诱导的神经毒性的影响。
结果表明，七氟醚暴露增加了海马体中死亡神经元的数量，同时上调了SAP130，并诱导了小胶质细胞活化及细胞因子产生。这些变化仅发生在神经元-小胶质细胞共培养系统中，而在神经元或小胶质细胞单培养中未发生。中和SAP130或通过药理学方法抑制Syk可通过抑制SAP130/Mincle信号通路减少小胶质细胞活化和神经元细胞死亡。
这些发现表明，SAP130/Mincle轴在七氟醚诱导的神经毒性中的神经元死亡和小胶质细胞活化中起关键作用。针对该轴可能成为减轻七氟醚神经毒性作用的潜在治疗策略。
