Abstract：
Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fine motor control difficulties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was significantly downregulated in the medial prefrontal cortex of young mice after multiple sevoflurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identified as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.
摘要：
包括儿童梅奥麻醉安全性（MASK）研究在内的临床研究发现，接受多次麻醉的儿童可能有更高的精细运动控制困难的风险。然而,潜在的机制仍然难以捉摸。这里,我们报道促红细胞生成素受体（EPOR），与吞噬活性相关的小胶质细胞受体，在多次七氟醚麻醉暴露后，幼鼠内侧前额叶皮质显著下调。重要的是,我们发现抑制促红细胞生成素（EPO）/EPOR信号轴导致小胶质细胞极化，过度的兴奋性突触修剪，以及多次麻醉暴露小鼠的异常精细运动控制技能，通过腹腔注射补充EPO衍生肽ARA290可以完全逆转上述情况。一起,在这项研究中，小胶质细胞EPOR被确定为调节早期突触发育的关键介质，影响七氟醚诱导的精细运动功能障碍。此外，ARA290可能通过靶向EPO/EPOR信号通路作为一种新的治疗全身麻醉神经毒性的方法。
