七氟醚是儿科患者常用的吸入麻醉剂，据报道，多次接触七氟醚会增加患神经认知障碍的风险。 N6-甲基腺苷 (m6A) 作为真核生物中最常见的 mRNA 修饰，已成为涉及突触可塑性、学习和记忆以及神经发育过程中大脑功能的关键调节因子。然而，m6A RNA 甲基化在多种七氟醚暴露引起的发育神经毒性中的相关性仍然难以捉摸。在此，我们使用 m6A 测序 (m6A-seq) 和 RNA 测序 (RNA-seq) 评估了接受多次七氟醚暴露的小鼠海马中的全基因组 m6A RNA 修饰和基因表达。我们发现了 19 个在 m6A 甲基化修饰和海马差异表达方面存在差异的基因。在这些基因中，我们确定共有9个差异表达基因可能与多次七氟醚诱发的发育神经毒性的发生密切相关。我们进一步发现，接受多次七氟醚暴露的小鼠海马体中 alkB 同源物 5 (ALKBH5) 增加，但甲基转移酶样 3 (METTL3) 和肾母细胞瘤 1 相关蛋白 (WTAP) 没有增加。 IOX1作为ALKBH5的抑制剂，显着改善了多次七氟醚暴露引起的小鼠学习记忆缺陷，减少了海马神经元损伤。目前的研究揭示了 m6A 甲基化修饰和 m6A 相关调节剂在七氟烷诱发的认知障碍中的作用，这可能为识别吸入麻醉剂诱发的发育性神经毒性的生物标志物和治疗策略提供新的见解。© 2024 美国实验学会联合会生物学。

Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6-Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure-induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome-wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A-sequencing (m6A-seq) and RNA-sequencing (RNA-seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase-like 3 (METTL3) and Wilms tumor 1-associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A-related regulators in sevoflurane-induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic-induced developmental neurotoxicity.© 2024 Federation of American Societies for Experimental Biology.