Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
Neurotoxicol Teratol. 2019 Jul-Aug;74:106813. doi: 10.1016/j.ntt.2019.106813. Epub 2019 Jun 26.
Animal studies have demonstrated that multiple exposures to sevoflurane during the postnatal period lead to impaired synaptogenesis and cognitive deficits in adulthood. However, the underlying mechanisms remain unclear. Histone deacetylase 6 (HDAC6), a unique isoform of class II histone deacetylases (HDACs), mediates diverse cellular processes such as cell survival, inflammation, intracellular trafficking and protein degradation. Varieties of literature suggest the importance of HDAC6 in memory formation and abnormal neurodegenerative diseases. The aim of this study was to investigate potential roles of HDAC6 in sevoflurane-induced developmental neurotoxicity. Postnatal day 7 (P7) rat pups were randomly assigned to control group and sevoflurane group (n = 6 for each group). They were exposed to 60% oxygen and 40% nitrogen with or without 3% sevoflurane for 2 h daily for three consecutive days (P7, P8 and P9). Immediately after the last exposure, both hippocampi were harvested for detection of HDAC6 expression and activity. Next, P7 rat pups were divided into control group, sevoflurane group, sevoflurane + Tubastatin A, and Tubastatin A groups (n = 6 for each group in molecular experiments; n = 16 for each group in behavioral testing). A dose of 25 mg/kg body weight of Tubastatin A (a selective HDAC6 inhibitor) were administrated intraperitoneally 30 min prior to each sevoflurane exposure. After treatments, expression levels of synaptophysin and postsynaptic density 95 protein (PSD95) were quantified using Western blot, and synaptic ultrastructure was evaluated by transmission electron microscopy. Additional pups were raised until P49 to measure cognitive performance using the Morris water maze test. Our results demonstrated that multiple sevoflurane exposures enhanced HDAC6 expression and activity in hippocampi of the developing brain. Tubastatin A ameliorated sevoflurane-induced decreases in synaptophysin and PSD95 expression during development, as well as synaptic ultrastructural damage and cognitive deficits in adulthood. In conclusion, HDAC6 is involved in the developmental neurotoxicity caused by multiple sevoflurane exposures and its inhibition may prevent related damage.
动物研究表明，在发育期多次接触七氟醚会导致成年后突触生成受损和认知缺陷。然而，其潜在机制尚不清楚。组蛋白去乙酰化酶 6（HDAC6）是 II 类组蛋白去乙酰化酶（HDACs）的独特同工酶，介导多种细胞过程，如细胞存活、炎症、细胞内运输和蛋白质降解。大量文献表明 HDAC6 在记忆形成和异常神经退行性疾病中具有重要作用。本研究旨在探讨 HDAC6 在七氟醚诱导的发育性神经毒性中的潜在作用。将出生后 7 天（P7）的大鼠幼崽随机分为对照组和七氟醚组（每组 6 只）。它们每天接受 60%氧气和 40%氮气，同时或不接受 3%七氟醚，连续 3 天（P7、P8 和 P9），每次 2 小时。最后一次暴露后，立即采集双侧海马用于检测 HDAC6 的表达和活性。接下来，将 P7 大鼠幼崽分为对照组、七氟醚组、七氟醚+Tubastatin A 组和 Tubastatin A 组（分子实验每组 6 只，行为测试每组 16 只）。在每次暴露七氟醚前 30 分钟，腹腔内给予 25mg/kg 体重的 Tubastatin A（一种选择性 HDAC6 抑制剂）。处理后，通过 Western blot 定量检测突触小体相关蛋白和突触后密度蛋白 95（PSD95）的表达水平，通过透射电镜评估突触超微结构。其余幼崽饲养至 P49，使用 Morris 水迷宫测试评估认知表现。我们的结果表明，多次七氟醚暴露会增强发育期大脑中海马的 HDAC6 表达和活性。Tubastatin A 可改善七氟醚诱导的发育过程中突触小体相关蛋白和 PSD95 表达的降低，以及成年后的突触超微结构损伤和认知缺陷。总之，HDAC6 参与了多次七氟醚暴露引起的发育性神经毒性，其抑制可能预防相关损伤。
