Role of histone acetylation in long-term neurobehavioral effects of neonatal Exposure to sevoflurane in rats

• Published in: Neurobiology of disease Vol. 91; pp. 209 - 220
• Main Authors: Jia, Min, Liu, Wen-Xue, Yang, Jiao-Jiao, Xu, Ning, Xie, Ze-Min, Ju, Ling-Sha, Ji, Mu-Huo, Martynyuk, Anatoly E, Yang, Jian-Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2016; Elsevier
• Subjects: Acetylation - drug effects; Animals; Brain-Derived Neurotrophic Factor - metabolism; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Histone acetylation; Histones - metabolism; Maternal Deprivation; Maternal separation; Methyl Ethers - pharmacology; Microtubule-Associated Proteins - metabolism; Neonatal rats; Neurology; Proto-Oncogene Proteins c-fos - metabolism; Rats, Sprague-Dawley; Sevoflurane; Synaptic plasticity; Time; Morris water maze; fear conditioning; Sev; sodium dodecyl sulfate polyacrylamide gel electrophoresis; Neonatal rats; phosphate-buffered saline; NaB; CBP; open field; CREB; MAP2; OF; Synaptic plasticity; histone deacetylases; CREB binding protein; brain-derived neurotrophic factor; Tris-buffered saline and Tween 20; maternal separation; PBS; MWM; sodium butyrate; BDNF; MS; TBST; Histone acetylation; SDS-PAGE; cyclic-AMP response element binding protein; sevoflurane; FC; microtubule-associated protein 2; Hippocampus; HDAC; Sevoflurane; Maternal separation
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2016.03.017

Abstract Human studies, and especially laboratory studies, provide evidence that early life exposure to general anesthesia may affect neurocognitive development via largely unknown mechanisms. We explored whether hippocampal histone acetylation had a role in neurodevelopmental effects of sevoflurane administered to neonatal rats. Male Sprague–Dawley rats were exposed to 3% sevoflurane or were subjected to maternal separation only for 2 h daily at postnatal days 6, 7, and 8. The histone deacetylase inhibitor, sodium butyrate (250 mg/kg, intraperitoneally), or saline was administered starting 2 h prior to anesthesia or maternal separation and continued daily until the end of behavioral tests, which were performed between postnatal days 33 and 50. Upon completion of the behavioral tests, the brain tissues were harvested for further analysis. Rats neonatally exposed to sevoflurane exhibited decreased freezing time in the fear conditioning contextual test and increased escape latency, decreased time in target quadrant, and number of platform crossings in the Morris water maze test. The sevoflurane-exposed rats had lower hippocampal density of dendritic spines, reduced levels of the brain-derived neurotrophic factor, c-fos protein, microtubule-associated protein 2, synapsin1, postsynaptic density protein 95, pCREB/CREB, CREB binding protein, and acetylated histones H3 and H4, and increased levels of histone deacetylases 3 and 8. These neurobehavioral abnormalities were normalized in the sevoflurane-exposed rats treated with sodium butyrate. Our findings provide evidence that neonatal exposure to sevoflurane induces neurobehavioral abnormalities and long-lasting alterations in histone acetylation; normalization of histone acetylation may alleviate the neurodevelopmental side effects of the anesthetic.