Zhang Qi, Li Yanan, Zhang Jiajie, Cui Yunyi, Sun Suzhen, Chen Wei, Shi Lei, Zhang Yingze, Hou Zhiyong
Postdoctoral Mobile Station of the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, PR China; Department of Anesthesiology, Hebei Children's Hospital Affiliated to Hebei Medical University, Hebei, 050031, PR China; Key Laboratory of Pediatric Epilepsy and Neurological Disorders of Hebei Province, PR China.
Department of Anesthesiology, The Third Hospital of Hebei Medical University, Hebei, PR China.
Free Radic Biol Med. 2025 Feb 1;227:12-26. doi: 10.1016/j.freeradbiomed.2024.11.039. Epub 2024 Nov 22.
Increasing numbers of animal studies have shown that repeat sevoflurane exposure during developmental stage may lead to long-term cognitive impairment. Nevertheless, the exact pathogenesis remains unclear. Interleukin 17A (IL-17A) has been associated with cognitive decline in various neurological disorders. Here we found that the expression of IL-17A was up-regulated in hippocampus of sevoflurane exposed neonatal mice. Genetic deletion of IL-17A or inhibition of IL-17A improved behavioral function and down-regulated neuroinflammation related genes, interleukin 1β (IL-1β), interleukin 6 (IL-6), Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) in hippocampus of sevoflurane exposed neonatal mice. Moreover, negative regulation of IL-17A/Interleukin 17A receptor(IL-17RA) promoted the extracellular signal-regulated protein kinase (ERK) signaling pathway and nucleation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB) in neurons of cognitive impaired mice. Knockdown of IL-17A in vivo identified neurons-localized IL-17A as a major factor in neuroinflammation and neurodevelopment. Collectively, our results suggested that IL-17A was required for the pathogenesis of neuroinflammatory response and identify IL-17A as a potential therapeutic target for cognitive impairment exposed by general anesthetics during infancy.
越来越多的动物研究表明，发育阶段反复接触七氟醚可能导致长期认知障碍。然而，确切的发病机制仍不清楚。白细胞介素17A（IL-17A）与多种神经系统疾病的认知功能下降有关。在此，我们发现七氟醚暴露的新生小鼠海马中IL-17A的表达上调。IL-17A基因缺失或IL-17A抑制改善了行为功能，并下调了七氟醚暴露的新生小鼠海马中与神经炎症相关的基因，白细胞介素1β（IL-1β）、白细胞介素6（IL-6）、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶2（NOX2）和NADPH氧化酶4（NOX4）。此外，IL-17A/白细胞介素17A受体（IL-17RA）的负调控促进了认知受损小鼠神经元中细胞外信号调节蛋白激酶（ERK）信号通路和环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）的核化。体内敲低IL-17A确定神经元定位的IL-17A是神经炎症和神经发育的主要因素。总的来说，我们的结果表明IL-17A是神经炎症反应发病机制所必需的，并确定IL-17A是婴儿期全身麻醉暴露所致认知障碍的潜在治疗靶点。
