Zhang Junjie, Xiong Rui, Su Yujuan, Li Haisu, Xu Ying
Department of Anesthesiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan Second Road, Chongging 400014, China; Chongqing Key Laboratory of Pediatrics, Chongqing, China.
Department of Anesthesiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan Second Road, Chongging 400014, China.
J Affect Disord. 2025 Jun 8;389:119640. doi: 10.1016/j.jad.2025.119640.
Esketamine is increasingly used to induce general anesthesia in pediatric populations. However, its neurological effects on healthy individuals-especially during early developmental stages-remain a topic of ongoing debate. In particular, concerns persist regarding its impact on the developing brain at extreme ages. Furthermore, the molecular mechanisms underlying these effects have not yet been fully elucidated.
Neonatal mice on postnatal days (P) 8, 10, and 12 received intraperitoneal injections of either sodium chloride or esketamine. Cognitive performance was assessed beginning at P56 using the Novel Object Recognition and Morris Water Maze tests to evaluate recognition memory and spatial learning, respectively. Hippocampal tissue samples were harvested at P14, P28, and P56 to investigate changes in molecular biomarkers. To explore the mechanistic role of Kcnq2, pharmacological inhibition was achieved using the selective antagonist XE991, while genetic suppression was performed using an adeno-associated virus-mediated knockdown approach.
Repeated esketamine exposure during early postnatal development led to significant hippocampal injury, including the downregulation of glutamatergic neuronal markers and the onset of persistent cognitive dysfunction in adolescent mice. These adverse outcomes were strongly associated with elevated expression of Kcnq2 in the hippocampus. Both pharmacological blockade and genetic knockdown of Kcnq2 effectively mitigated the esketamine-induced cognitive deficits. Western blotting further revealed that inhibition of Kcnq2 restored the phosphorylation levels of Akt1 and glycogen synthase kinase-3β, which were otherwise downregulated following esketamine exposure.
Our findings demonstrate that repeated esketamine administration during critical periods of brain development results in long-lasting cognitive impairments, which are mediated by the upregulation of Kcnq2 expression in the hippocampus. Mechanistically, activation of Kcnq2 appears to drive the dephosphorylation of key signaling molecules within the Akt1/GSK-3β pathway. This study provides compelling experimental evidence of the neurotoxic potential of esketamine in developing brains and identifies Kcnq2 as a novel therapeutic target for preventing anesthesia-related cognitive deficits in pediatric populations.
艾司氯胺酮越来越多地用于诱导儿科患者的全身麻醉。然而，其对健康个体（尤其是在早期发育阶段）的神经学影响仍是一个持续争论的话题。特别是，关于其在极端年龄对发育中大脑的影响的担忧仍然存在。此外，这些影响背后的分子机制尚未完全阐明。
出生后第8、10和12天的新生小鼠接受腹腔注射氯化钠或艾司氯胺酮。从出生后第56天开始，使用新物体识别和莫里斯水迷宫测试分别评估认知能力，以评估识别记忆和空间学习能力。在出生后第14、28和56天采集海马组织样本，以研究分子生物标志物的变化。为了探究Kcnq2的机制作用，使用选择性拮抗剂XE991实现药理学抑制，同时使用腺相关病毒介导的敲低方法进行基因抑制。
出生后早期发育期间反复接触艾司氯胺酮导致显著的海马损伤，包括谷氨酸能神经元标志物的下调以及青春期小鼠持续性认知功能障碍的出现。这些不良后果与海马中Kcnq2表达的升高密切相关。Kcnq2的药理学阻断和基因敲低均有效减轻了艾司氯胺酮诱导的认知缺陷。蛋白质印迹进一步显示，抑制Kcnq2可恢复Akt1和糖原合酶激酶-3β的磷酸化水平，而在接触艾司氯胺酮后它们原本会下调。
我们的研究结果表明，在大脑发育的关键时期反复给予艾司氯胺酮会导致长期的认知障碍，这是由海马中Kcnq2表达的上调介导的。从机制上讲，Kcnq2的激活似乎驱动了Akt1/GSK-3β途径内关键信号分子的去磷酸化。这项研究提供了令人信服的实验证据，证明艾司氯胺酮对发育中大脑具有神经毒性潜力，并确定Kcnq2是预防儿科患者麻醉相关认知缺陷的新治疗靶点。
