Department of Anesthesiology, the First Affiliated Hospital, Nanchang University, Nanchang, China.
Department of Anesthesiology, the Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
J Cell Mol Med. 2018 May;22(5):2600-2611. doi: 10.1111/jcmm.13524. Epub 2018 Feb 20.
Propofol is widely used in clinical practice, including non-obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post-natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.
丙泊酚广泛应用于临床实践，包括孕妇的非产科手术。此前，我们发现妊娠大鼠第三期（E18）丙泊酚麻醉会导致子代大鼠学习和记忆功能受损，但早期妊娠暴露丙泊酚会怎样，其潜在机制是什么？组蛋白乙酰化在突触可塑性中起重要作用。在这项研究中，我们在妊娠大鼠早期（E7）给予丙泊酚。在产后第 30 天，通过 Morris 水迷宫（MWM）测试检测子代的学习和记忆功能。在每次 MWM 试验前 2 小时，给予子代组蛋白去乙酰化酶 2（HDAC2）抑制剂 SAHA、Senegenin（SEN，中药）、Hippyragranin（HGN）反义寡核苷酸（HGNA）或载体。通过 Western blot 或免疫荧光试验测定子代海马组织中 HDAC2、乙酰化组蛋白 3（H3）和 4（H4）、环磷酸腺苷反应元件结合蛋白（CREB）、N-甲基-D-天冬氨酸受体（NMDAR）2 亚基 B（NR2B）、HGN 和突触小体蛋白的蛋白水平。结果发现，妊娠大鼠 E7 时丙泊酚输注导致子代学习和记忆受损，增加了 HDAC2 和 HGN 的蛋白水平，降低了乙酰化 H3 和 H4 及磷酸化 CREB、NR2B 和突触小体蛋白的水平。HDAC2 抑制剂 SAHA、Senegenin 或 HGN 反义寡核苷酸逆转了所有这些变化。因此，目前的结果表明，早期妊娠暴露于丙泊酚会通过抑制组蛋白乙酰化来损害子代的学习和记忆。SAHA、Senegenin 和 HGN 反义寡核苷酸可能对丙泊酚的不良作用具有治疗价值。
