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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.


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(a) Isoflurane prolonged the escape latency (EL) of wild type neonatal mice compared with the wild type control group. The effects of time and group differences between the two groups were significant; P < 0.05. (b and d) Isoflurane did not prolong the EL of either FAS-knockout or FASL-knockout mice compared with wild type neonatal mice treated with isoflurane. The effects of time and group differences between the two groups were significant. (c and e) EL of the wild type control group and isoflurane-treated FAS- and FASL-knockout mice were not significantly different. (f) Isoflurane significantly reduced the platform crossing times of wild type neonatal mice compared with wild type control mice and isoflurane-treated FAS- and FASL-knockout mice.
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fig5: (a) Isoflurane prolonged the escape latency (EL) of wild type neonatal mice compared with the wild type control group. The effects of time and group differences between the two groups were significant; P < 0.05. (b and d) Isoflurane did not prolong the EL of either FAS-knockout or FASL-knockout mice compared with wild type neonatal mice treated with isoflurane. The effects of time and group differences between the two groups were significant. (c and e) EL of the wild type control group and isoflurane-treated FAS- and FASL-knockout mice were not significantly different. (f) Isoflurane significantly reduced the platform crossing times of wild type neonatal mice compared with wild type control mice and isoflurane-treated FAS- and FASL-knockout mice.

Mentions: The MWM was used to study any hippocampal-dependent learning and memory changes elicited by isoflurane. The escape latency of wild type mice was clearly prolonged after isoflurane treatment (Figure 5(a)). There was no significant difference in escape latency between the FAS- and FASL-knockout mice with isoflurane anesthesia and the wild type control mice (Figures 5(c) and 5(e)). However, the escape latency was drastically shortened in the FAS- and FASL-knockout mice treated with isoflurane compared with the wild type isoflurane group (Figures 5(b) and 5(d)). Two-way ANOVA showed that loss of either FAS or FASL attenuates the prolongation of escape latency induced by isoflurane. Comparing platform crossings among the four groups (wild type control group, wild type isoflurane group, and FAS- and FASL-knockout mice treated with isoflurane) showed that wild type mice treated with isoflurane had fewer crossings compared with the other three groups (Figure 5(f)).


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) Isoflurane prolonged the escape latency (EL) of wild type neonatal mice compared with the wild type control group. The effects of time and group differences between the two groups were significant; P < 0.05. (b and d) Isoflurane did not prolong the EL of either FAS-knockout or FASL-knockout mice compared with wild type neonatal mice treated with isoflurane. The effects of time and group differences between the two groups were significant. (c and e) EL of the wild type control group and isoflurane-treated FAS- and FASL-knockout mice were not significantly different. (f) Isoflurane significantly reduced the platform crossing times of wild type neonatal mice compared with wild type control mice and isoflurane-treated FAS- and FASL-knockout mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644536&req=5

fig5: (a) Isoflurane prolonged the escape latency (EL) of wild type neonatal mice compared with the wild type control group. The effects of time and group differences between the two groups were significant; P < 0.05. (b and d) Isoflurane did not prolong the EL of either FAS-knockout or FASL-knockout mice compared with wild type neonatal mice treated with isoflurane. The effects of time and group differences between the two groups were significant. (c and e) EL of the wild type control group and isoflurane-treated FAS- and FASL-knockout mice were not significantly different. (f) Isoflurane significantly reduced the platform crossing times of wild type neonatal mice compared with wild type control mice and isoflurane-treated FAS- and FASL-knockout mice.
Mentions: The MWM was used to study any hippocampal-dependent learning and memory changes elicited by isoflurane. The escape latency of wild type mice was clearly prolonged after isoflurane treatment (Figure 5(a)). There was no significant difference in escape latency between the FAS- and FASL-knockout mice with isoflurane anesthesia and the wild type control mice (Figures 5(c) and 5(e)). However, the escape latency was drastically shortened in the FAS- and FASL-knockout mice treated with isoflurane compared with the wild type isoflurane group (Figures 5(b) and 5(d)). Two-way ANOVA showed that loss of either FAS or FASL attenuates the prolongation of escape latency induced by isoflurane. Comparing platform crossings among the four groups (wild type control group, wild type isoflurane group, and FAS- and FASL-knockout mice treated with isoflurane) showed that wild type mice treated with isoflurane had fewer crossings compared with the other three groups (Figure 5(f)).

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