title: Isoflurane Damages the Developing Brain of Mice and Induces Subsequent Learning and Memory Deficits through FASL-FAS Signaling.
abstract: Background. Isoflurane disrupts brain development of neonatal mice, but its mechanism is unclear. We explored whether isoflurane damaged developing hippocampi through FASL-FAS signaling pathway, which is a well-known pathway of apoptosis. Method. Wild type and FAS- or FASL-gene-knockout mice aged 7 days were exposed to either isoflurane or pure oxygen. We used western blotting to study expressions of caspase-3, FAS (CD95), and FAS ligand (FASL or CD95L) proteins, TUNEL staining to count apoptotic cells in hippocampus, and Morris water maze (MWM) to evaluate learning and memory. Result. Isoflurane increased expression of FAS and FASL proteins in wild type mice. Compared to isoflurane-treated FAS- and FASL-knockout mice, isoflurane-treated wild type mice had higher expression of caspase-3 and more TUNEL-positive hippocampal cells. Expression of caspase-3 in wild isoflurane group, wild control group, FAS/FASL-gene-knockout control group, and FAS/FASL-gene-knockout isoflurane group showed FAS or FASL gene knockout might attenuate increase of caspase-3 caused by isoflurane. MWM showed isoflurane treatment of wild type mice significantly prolonged escape latency and reduced platform crossing times compared with gene-knockout isoflurane-treated groups. Conclusion. Isoflurane induces apoptosis in developing hippocampi of wild type mice but not in FAS- and FASL-knockout mice and damages brain development through FASL-FAS signaling.
authors.affiliation: Department of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D007530:Isoflurane / Q000009:adverse effects*; D007858:Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019014:fas Receptor; D007530:Isoflurane; D053148:Caspase 3