title: Chronic exposure of gestation rat to sevoflurane impairs offspring brain development.
abstract: Recently it was demonstrated that the exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors can trigger widespread apoptotic neurodegeneration. Sevoflurane is a new inhalation anesthetic agent commonly used in the clinic. Here we address whether sevoflurane could induce neurotoxicity in the developing brain. Sevoflurane was administered to rats before pregnancy and pregnant rats on embryonic days E6, E10, E14, and E18 1MAC for 6 h, and we employed histopathological, immunochemistry, semiquantitative RT-PCR, and Western blot to investigate the effect of the exposure of pregestation and gestation rats to sevoflurane on the offspring brain development. The results showed that the exposure of gestation but not pregestation rats to sevoflurane-induced extensive apoptotic neurodegeneration in the hippocampus of offspring at P0, P7, and P14, accompanied by altered expression of casepase-3, GAP-43, nNOS, NMDAR1, NMDAR2A, and NMDAR2B. Furthermore, upregulation of PKCα and p-JNK and downregulation of p-ERK and FOS protein levels were observed in the hippocampus of offspring at P0, P7, and P14 from rats exposed to sevoflurane at gestation, but not pregestation. In summary, our data suggest that sevoflurane induces developmental neurotoxicity in rats and this may be attributed to the upregulation of PKCα and p-JNK and downregulation of p-ERK and FOS protein in the hippocampus.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
authors.forename: Yuheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Cheng
authors.forename: Guibo
authors.initials: G
authors.lastname: Liu
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Tian
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Tu
authors.forename: Junke
authors.initials: J
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001784:Blood Gas Analysis; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008738:Methyl Ethers / Q000633:toxicity*; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D019922:GAP-43 Protein; D008738:Methyl Ethers; D016761:Oncogene Proteins v-fos; D016194:Receptors, N-Methyl-D-Aspartate; D000077149:Sevoflurane; D052248:Nitric Oxide Synthase Type I; D051571:Protein Kinase C-alpha