Abstract：
The neurodevelopmental toxicity of anesthetics has been confirmed repeatedly, and esketamine is now widely used in pediatric surgeries. Oligodendrocyte precursor cells (OPCs) evolved into mature oligodendrocytes (OLs) and formed myeline sheath during the early brain development. In this study, we investigated whether esketamine exposure interrupted development of OPCs and induced hypomyelination in rats. Further we explored the roles of PI3K/Akt phosphorylation in OPCs development and myelination. Sprague Dawley rats with different ages (postnatal day (P) 1, 3, 7 and 12) were exposed to 40mg/kg esketamine. Progesterone treatment was given (16 mg/kg per day for 3 days) 24 h after esketamine exposure via the intraperitoneal route. Corpus callosum tissues were collected at P8 or P14 for western blot and immunofluorescence analyses. Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) expression and CC1+ OLs number in corpus callosum. Esketamine exposure at P7 not only aggravated the mature OLs apoptosis, also decreased the OPCs proliferation and differentiation, which was related with dephosphorylation of PI3K/Akt. Progesterone was able to promote OPCs differentiation and ameliorate esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation. Stage-dependent abnormality of OPCs/OLs after esketamine leads to the esketamine-induced hypomyelination. Esketamine interrupted OPCs evolution via PI3K/Akt signaling pathway, which can be ameliorated by progesterone.
摘要：
麻醉药的神经发育毒性已被反复证实,和艾氯胺酮现在广泛用于儿科手术。少突胶质前体细胞(OPCs)在早期脑发育过程中进化成成熟的少突胶质细胞(OLs)并形成脊髓鞘。在这项研究中,我们调查了在大鼠中暴露esketamine是否会中断OPCs的发育并诱导骨髓增生异常。我们进一步探讨了PI3K/Akt磷酸化在OPCs发育和髓鞘形成中的作用。将不同年龄（出生后第1、3、7和12天）的SpragueDawley大鼠暴露于40mg/kg的艾氯胺酮。在通过腹膜内途径暴露esketamine后24小时给予孕酮治疗（每天16mg/kg，持续3天）。在P8或P14处收集call体组织用于蛋白质印迹和免疫荧光分析。在P7和P12时暴露Esketamine显着降低了call体的髓鞘碱性蛋白（MBP）表达和CC1OLs数量。在P7时暴露Esketamine不仅加重了成熟OLs的凋亡，也降低了OPCs的增殖和分化，这与PI3K/Akt的去磷酸化有关。孕酮能够通过增强PI3K/Akt磷酸化来促进OPCs的分化并改善艾氯胺酮诱导的髓鞘减少。艾氯胺酮后OPCs/OLs的阶段依赖性异常导致艾氯胺酮诱导的髓鞘减少。Esketamine通过PI3K/Akt信号通路中断OPCs的进化，孕酮可以改善。
