Suberoylanilide Hydroxamic Acid Attenuates Cognitive Impairment in Offspring Caused by Maternal Surgery during Mid-pregnancy

Abstract

It is known that commonly-used anesthetics can cause long-term neurotoxicity in the developing brain. Some pregnant women have to experience non-obstetric surgery during pregnancy under general anesthesia. It is known that maternal exposure to sevoflurane, isoflurane, propofol and ketamine causes cognitive deficits in offspring. Histone acetylation has been implicated in synaptic plasticity, and abnormal histone acetylation contributes to the neonatal sevoflurane exposure induced deficits in hippocampus-dependent learning and memory. The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was shown to attenuate the sevoflurane-induced deficits. Propofol is commonly used in non-obstetric procedures on pregnant women. Recent evidence shows that propofol also causes neurotoxicity in developing brains. For example, previous studies in our laboratory showed that maternal propofol exposure in pregnancy impairs learning and memory in offspring by disturbing histone acetylation. The present study aims to investigate whether SAHA could also attenuate propofol-induced learning and memory deficits in offspring caused by maternal surgery during mid-pregnancy. Maternal rats were exposed to propofol or underwent abdominal surgery under propofol anesthesia during middle pregnancy. The learning and memory abilities of the offspring rats were assessed using Morris water maze (MWM) test. The protein levels of histone deacetylase 2 (HDAC2), phosphorylated cAMP response-element binding (p-CREB),brain derived neurotriphic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) in the hippocampus of the offspring rats were evaluated by immunofluorescence staining and western blot. Hippocampal neuroapoptosis was detected by TUNEL staining. Our results showed that maternal propofol exposure during middle pregnancy impaired the water-maze learning and memory of the offspring rats, increased the protein level of HDAC2 and reduced the protein levels of p-CREB,BDNF and p-TrkB in the hippocampus of the offspring, and such effects were exacerbated by surgery. SAHA alleviated the cognitive dysfunction and rescued the changes in the protein levels of p-CREB, BDNF and p-TrkB induced by maternal propofol exposure alone or maternal propofol exposure plus surgery. Therefore, SAHA could be a potential and promising agent for treating the learning and memory deficits in offspring caused by maternal nonobstetric surgery under propofol aneshtesia.