Abstract：
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.
摘要：
七氟醚,作为儿科患者常用的吸入麻醉剂，据报道，多次七氟烷暴露与发生神经认知障碍的风险更大。N6-甲基腺苷（m6A），作为真核生物中最常见的mRNA修饰，已经成为涉及突触可塑性的过程中大脑功能的关键调节剂，学习和记忆，和神经发育。然而，m6ARNA甲基化在七氟烷多次暴露诱导的发育神经毒性中的相关性仍然难以捉摸.在这里，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的全基因组m6ARNA修饰和海马中的基因表达.我们发现了19个基因在海马中m6A甲基化修饰和差异表达方面存在差异。在这些基因中,我们确定共有9个差异表达基因可能与七氟烷多次暴露引起的发育神经毒性的发生密切相关。我们进一步发现alkB同源物5(ALKBH5)，但不是甲基转移酶样3（METTL3）和Wilms肿瘤1相关蛋白（WTAP），在接受多次七氟烷暴露的小鼠海马中增加。而IOX1作为ALKBH5的抑制剂，可显著改善七氟烷多次暴露引起的小鼠学习记忆缺陷，减轻海马神经元损伤。目前的研究揭示了m6A甲基化修饰和m6A相关调节因子在七氟醚诱导的认知障碍中的作用。这可能为识别吸入麻醉药诱导的发育神经毒性的生物标志物和治疗策略提供新的见解。
