title: S6 inhibition contributes to isoflurane neurotoxicity in the developing brain.
abstract: Postnatal isoflurane exposure leads to neurodegeneration and deficits of spatial learning and memory in the adulthood. However, the underlying mechanisms remain unclear. Ribosomal protein S6 is demonstrated to play a pivotal role in control of cell survival, protein synthesis and synaptogenesis for brain development. In this study, the possible role of S6 and its upstream signaling pathways in the developmental neurotoxicity of isoflurane was evaluated using models of primary cultured hippocampal neurons and postnatal day 7 rats. We found that isoflurane decreased IGF-1 level and suppressed activation of IGF-1 receptor, sequentially inhibiting S6 activity via IGF-1/MEK/ERK and IGF-1/PI3K/Akt signaling pathways. S6 inhibition enhanced isoflurane-induced decreased Bcl-xL and increased cleaved caspase-3 and Bad, also reduced PSD95 expression and aggravated deficits of spatial learning and memory. S6 activation could reverse the damages above. These results indicate that S6 inhibition, led by suppression of upstream IGF-1/MEK/ERK and IGF-1/PI3K/Akt signaling pathways, is involved in the neuroapoptosis, synaptogenesis impairment and spatial learning and memory decline caused by postnatal isoflurane exposure. S6 activation may exhibit protective potential against developmental neurotoxicity of isoflurane.
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Xue
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Anatomy, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. Electronic address: yubuwei@hotmail.com.
authors.forename: Buwei
authors.initials: B
authors.lastname: Yu
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000254:growth & development*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007530:Isoflurane / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced / Q000523:psychology; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000037:antagonists & inhibitors*
chemical_list: D018685:Anesthetics, Inhalation; D038601:Ribosomal Protein S6; D007530:Isoflurane
keywords: Isoflurane; Learning and memory; Neuroapoptosis; Ribosomal protein S6; Synaptogenesis