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Isoflurane Damages the Developing Brain of Mice and Induces Subsequent Learning and Memory Deficits through FASL-FAS Signaling.

Yi X, Cai Y, Li W - Biomed Res Int (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.

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.

No MeSH data available.


Related in: MedlinePlus

(a, b) Heat map of significantly upregulated genes (a) or downregulated genes (b) in primary cortical neurons treated with isoflurane. Diagrams depicting differentially expressed genes were grouped into distinct categories based on the function of encoded proteins shown on the left. (c) Quantitative pathway analysis using gene set enrichment showed the enrichment of FAS signaling in isoflurane-treated primary cortical neurons. (d) Heat map of microarray analysis demonstrated that the FAS signaling related transcripts were upregulated, including FAS and its ligand, FASL.
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fig1: (a, b) Heat map of significantly upregulated genes (a) or downregulated genes (b) in primary cortical neurons treated with isoflurane. Diagrams depicting differentially expressed genes were grouped into distinct categories based on the function of encoded proteins shown on the left. (c) Quantitative pathway analysis using gene set enrichment showed the enrichment of FAS signaling in isoflurane-treated primary cortical neurons. (d) Heat map of microarray analysis demonstrated that the FAS signaling related transcripts were upregulated, including FAS and its ligand, FASL.

Mentions: We first investigated the possible connection among isoflurane treatment, FASL-FAS signaling, and neurotoxicity. In primary cortical neurons, isoflurane upregulated the expression of genes like apoptosis-related 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)).


Isoflurane Damages the Developing Brain of Mice and Induces Subsequent Learning and Memory Deficits through FASL-FAS Signaling.

Yi X, Cai Y, Li W - Biomed Res Int (2015)

(a, b) Heat map of significantly upregulated genes (a) or downregulated genes (b) in primary cortical neurons treated with isoflurane. Diagrams depicting differentially expressed genes were grouped into distinct categories based on the function of encoded proteins shown on the left. (c) Quantitative pathway analysis using gene set enrichment showed the enrichment of FAS signaling in isoflurane-treated primary cortical neurons. (d) Heat map of microarray analysis demonstrated that the FAS signaling related transcripts were upregulated, including FAS and its ligand, FASL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644536&req=5

fig1: (a, b) Heat map of significantly upregulated genes (a) or downregulated genes (b) in primary cortical neurons treated with isoflurane. Diagrams depicting differentially expressed genes were grouped into distinct categories based on the function of encoded proteins shown on the left. (c) Quantitative pathway analysis using gene set enrichment showed the enrichment of FAS signaling in isoflurane-treated primary cortical neurons. (d) Heat map of microarray analysis demonstrated that the FAS signaling related transcripts were upregulated, including FAS and its ligand, FASL.
Mentions: We first investigated the possible connection among isoflurane treatment, FASL-FAS signaling, and neurotoxicity. In primary cortical neurons, isoflurane upregulated the expression of genes like apoptosis-related 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)).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai 200031, China.

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.

No MeSH data available.


Related in: MedlinePlus