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.
Highlights
Isoflurane is a commonly used clinical anesthetic because it is fast-acting, produces little irritability, and stabilizes hemodynamic status of patients
Isoflurane upregulated the expression of genes like apoptosisrelated genes and downregulated the expression of genes involved in learning and memory (Figures 1(a) and 1(b))
The activity of FASL-FAS signaling was verified through quantitative pathway analysis and the expression of proteins related to the signaling pathway was dramatically increased (Figures 1(c) and 1(d))
Summary
Isoflurane is a commonly used clinical anesthetic because it is fast-acting, produces little irritability, and stabilizes hemodynamic status of patients. Researchers showed many adverse effects caused by isoflurane on the developing brain especially in the embryonic period, neonatal period, and infancy. They concluded that isoflurane could increase neurodegeneration in the developing hippocampus of fetal rats [3]. Wild type and FAS- or FASL-gene-knockout mice aged 7 days were exposed to either isoflurane or pure oxygen. 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. 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
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