Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China.
FASEB J. 2024 Jul 31;38(14):e23793. doi: 10.1096/fj.202400664R.
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.
七氟醚作为小儿患者常用的吸入性麻醉剂，有报道称多次七氟醚暴露与神经认知障碍的风险增加有关。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等过程中大脑功能的关键调节因子。然而，m6A RNA 甲基化在多次七氟醚暴露诱导的发育性神经毒性中的相关性仍大多难以捉摸。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 个在海马中 m6A 甲基化修饰和差异表达存在差异的基因。在这些基因中，我们确定了总共 9 个差异表达基因可能与多次七氟醚暴露诱导的发育性神经毒性的发生密切相关。我们进一步发现，alkB 同源物 5（ALKBH5），而不是甲基转移酶样 3（METTL3）和 Wilms 肿瘤 1 相关蛋白（WTAP），在接受多次七氟醚暴露的小鼠海马中增加。并且 IOX1，作为 ALKBH5 的抑制剂，显著改善了多次七氟醚暴露诱导的小鼠海马中的学习和记忆缺陷，并减少了神经元损伤。本研究揭示了 m6A 甲基化修饰和 m6A 相关调控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剂诱导的发育性神经毒性的生物标志物和治疗策略提供新的思路。
