title: STAT3 degradation mediated by calcineurin involved in the neurotoxicity of isoflurane.
abstract: Isoflurane, a commonly used volatile anesthetic, causes widespread neuronal apoptosis in the developing brain of rodents. Signal transducer and activator of transcription-3 (STAT3) signaling is crucial for cell survival during the neural network establishment period. The aim of this study was to determine whether isoflurane would target STAT3 to deliver its neurotoxicity. Mice at postnatal day 7 and primary cortical neurons cultured for 5 days were treated with isoflurane. Our data showed that isoflurane exposure downregulated the STAT3 survival pathway in the brain of mice and in primary neurons, whereas the mRNA levels of STAT3 remained unchanged after isoflurane exposure. We found that inhibiting the activity of calcineurin, which specifically promotes STAT3 degradation, alleviated isoflurane-induced neural apoptosis. Further studies showed that isoflurane increased calcineurin activity and that the inositol 1,4,5-trisphosphate-sensitive Ca(2+) channel was involved in these isoflurane-induced molecular cascades. These findings suggest that isoflurane-induced neurotoxicity may stem from STAT3 degradation, partially through the activation of calcineurin.
authors.affiliation: aCenter for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu bDepartment of Biochemistry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Shiyu
authors.initials: S
authors.lastname: Song
authors.forename: Haiyan
authors.initials: H
authors.lastname: Min
authors.forename: Xiufang
authors.initials: X
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D015536:Down-Regulation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007530:Isoflurane; D019703:Calcineurin; D016559:Tacrolimus