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S6 inhibition contributes to isoflurane neurotoxicity in the developing brain.
Toxicol Lett. 2015 Mar 04; 233(2):102-13.TL

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+Show Affiliations

Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.Department of Anatomy, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. Electronic address: yubuwei@hotmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25597859

Citation

Li, Guohui, et al. "S6 Inhibition Contributes to Isoflurane Neurotoxicity in the Developing Brain." Toxicology Letters, vol. 233, no. 2, 2015, pp. 102-13.
Li G, Xue Q, Luo Y, et al. S6 inhibition contributes to isoflurane neurotoxicity in the developing brain. Toxicol Lett. 2015;233(2):102-13.
Li, G., Xue, Q., Luo, Y., Hu, X., & Yu, B. (2015). S6 inhibition contributes to isoflurane neurotoxicity in the developing brain. Toxicology Letters, 233(2), 102-13. https://doi.org/10.1016/j.toxlet.2014.11.026
Li G, et al. S6 Inhibition Contributes to Isoflurane Neurotoxicity in the Developing Brain. Toxicol Lett. 2015 Mar 4;233(2):102-13. PubMed PMID: 25597859.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - S6 inhibition contributes to isoflurane neurotoxicity in the developing brain. AU - Li,Guohui, AU - Xue,Qingsheng, AU - Luo,Yan, AU - Hu,Xiaodong, AU - Yu,Buwei, Y1 - 2015/01/15/ PY - 2014/10/01/received PY - 2014/11/18/revised PY - 2014/11/21/accepted PY - 2015/1/20/entrez PY - 2015/1/20/pubmed PY - 2015/4/14/medline KW - Isoflurane KW - Learning and memory KW - Neuroapoptosis KW - Ribosomal protein S6 KW - Synaptogenesis SP - 102 EP - 13 JF - Toxicology letters JO - Toxicol. Lett. VL - 233 IS - 2 N2 - 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/25597859/S6_inhibition_contributes_to_isoflurane_neurotoxicity_in_the_developing_brain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(14)01478-7 DB - PRIME DP - Unbound Medicine ER -