Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

Abstract

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.

Dexmedetomidine Ameliorates the Neurotoxicity of Sevoflurane on the Immature Brain Through the BMP/SMAD Signaling Pathway

“…However, emergency surgeries such as trauma surgery, emergency cesarean delivery and fetal intrauterine surgery make general anesthesia inevitable during pregnancy. Because most general anesthetics with strong lipid-solubility can pass across the placental barrier, maternal anesthesia can generate negative effects on the fetal nervous system, (Wang Y. et al, 2012; Zheng et al, 2013; Lin et al, 2018). The Food and Drug Agency (FDA) issued an official warning that children under 3 years of age or pregnant women in the third trimester who would undergo anesthesia for more than 3 h or more anesthesia procedures might exert adverse consequences of children’s brain development (Andropoulos and Greene, 2017).…”

The Role of Epigenetic Modifications in Neurotoxicity Induced by Neonatal General Anesthesia

“…The data upon were all tested on the postnatal 33 days, 1 h after the fear conditioning test. When explored the GA effects on the maternal-offspring module, the researchers indicated that infusion with propofol in maternal rats on gestational day-7 leads to impairment of learning and memory in off-spring, increased the protein levels of HDAC2, decreased the levels of acetylated H3K14 and H4K12 ( Lin et al, 2018b ). The different results of the different anesthetics suggest that the histone acetylation may have the drug specificity.…”

The mechanism of propofol in cancer development: An updated review

“…It is well known that epigenetic alterations or genetic modulation of epigenetic regulators plays important roles in carcinogenesis . Many studies show that the anticancer effect of propofol is potentially due to regulation of the epigenetic pathway in cancer …”

“…Liu et al. proved that propofol could affect the offspring's learning and memory by inhibiting histone acetylation . In 2017, Liu et al.…”

“…39 Liu et al proved that propofol could affect the offspring's learning and memory by inhibiting histone acetylation. 40 In 2017, Liu et al found that propofol could decrease the total HDAC activity and the levels of HDAC1, resulting in the inhibition of invasion, migration, and EMT in gastric cancer cells. 41 All these results suggest that propofol regulates cancer development by histone-mediated epigenetic regulation, but the exact mechanism needs further study.…”