Surgery Deteriorates The Learning And Memory Impairment In Rat Offspring Induced By Maternal Propofol Exposure During The Middle Pregnancy

Objective:Histone deacetylase HDAC2 could influence the learning and memory by cAMP response-element binding protein CREB regulating N-methyl-D-aspartate receptor NR2 B subunit.Our preliminary study showed that maternal propofol exposure during pregnancy impairs the learning and memory in rat offspring,but the roles of HDAC2-CREB-NR2 B signaling pathway in the impaired learning and memory induced by propofol exposure keep unknown.The aim of this study is to investigate the effects of maternal rats exposure to propofol combined with surgery during the middle pregnancy on the learning and memory of offspring and the roles of HDAC2-CREB-NR2 B signaling pathway in learning and memory of offspring.Methods:Female Sprague-Dawley(SD)rats were randomly assigned to propofol anesthesia(P4 group),propofol anesthesia combined with surgery(P4S group),control condition(C group)and intralipid(I group)groups.Maternal rats in group P4 received propofol anesthesia for 4 hours,whereas those in group P4 S received surgery under propofol anesthesia for 4 hours on gestational day 14(E14);Equal volumes(2ml/kg)of normal saline was given to rats in normal saline control group;Equal volumes(2ml/kg)of 20% intralipid was given to rats in intralipid group.The offspring born to each maternal rat were randomly subdivided into SAHA,Senegenin(SEN)and DMSO subgroups.Two hours before each Morris water maze(MWM)trial,90mg/kg HDAC2 inhibitor SAHA was given to the offspring in SAHA subgroup;15mg/kg Senegenin SEN was given to the offspring in SEN subgroup;Control solvent DMSO was given to those in the DMSO subgroup once per day for consecutive 7 day.Learning and memory was assessed using the MWM test on postnatal 30 day(P30).The expression of histone deacetylase 2(HDAC2),phosphorylated cAMP response-element binding protein(p-CREB),and N-methyl-D-aspartate receptor 2 subunit B(NR2B)protein in the hippocampus of offspring were detected by immunohistochemistry(IHC).The TUNEL staining was used to detect the neuroapoptosis in the hippocampus of offspring.Results:Maternal rats propofol exposure during the middle pregnancy could impaire the learning and memory of rat offspring,induce hippocampal neuroapoptosis,up-regulate HDAC2 expression levels and down-regulate the expression levels of p-CREB and NR2 B proteins in the hippocampus of offspring.Surgery deteriorated all the changes above.SAHA could alleviate the aforementioned changes but had no significant effect on the hippocampal neuroapoptosis of offspring.SEN could alleviate the learning and memory impairments,alleviate the changes of NR2 B expression levels and inhibit hippocampal neuroapoptosis of offspring,but had no significant effect on the expression levels of HDAC2 and NR2 B proteins.Conclusions:Propofol exposure in middle pregnancy impaired learning and memory of offspring via impairing the hippocampal neuron and HDAC2-CREB-NR2 B singaling pathway,Surgery deteriorated the learning and memory impairements via the aforementioned singnaling pathway.HDAC2 inhibitor SAHA could alleviate impaired learning and memory via HDAC2-CREB-NR2 B singaling pathway.Senegenin could alleviate the learning and memory impairements by reversing the expression levels of NR2 B protein,but the exact mechanism need further study.