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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 increased the number of TUNEL-positive cells in the hippocampi of wild type neonatal mice compared with wild type control mice. FAS knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FAS-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm. (b) FASL knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FASL-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm.
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fig4: (a) Isoflurane increased the number of TUNEL-positive cells in the hippocampi of wild type neonatal mice compared with wild type control mice. FAS knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FAS-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm. (b) FASL knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FASL-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm.

Mentions: We also determined the degree of neuronal apoptosis by counting TUNEL-positive cells in the hippocampus of mice exposed to isoflurane or oxygen treatment. Isoflurane significantly increased the number of TUNEL-positive cells in wild type mice compared to the wild control group (Figure 4). However, loss of either FAS or FASL occluded this isoflurane-dependent cell death in the hippocampus (Figures 4(a) and 4(b)). FAS/FASL-gene-knockout mice showed fewer apoptosis cells in hippocampus no matter whether they were in pure oxygen group or isoflurane group compared to wild isoflurane group.


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 increased the number of TUNEL-positive cells in the hippocampi of wild type neonatal mice compared with wild type control mice. FAS knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FAS-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm. (b) FASL knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FASL-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644536&req=5

fig4: (a) Isoflurane increased the number of TUNEL-positive cells in the hippocampi of wild type neonatal mice compared with wild type control mice. FAS knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FAS-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm. (b) FASL knockout had no effect on baseline TUNEL staining. Isoflurane did not increase TUNEL-positive cells in FASL-knockout mice compared to wild type isoflurane-treated mice. The scale bar represents 50 μm.
Mentions: We also determined the degree of neuronal apoptosis by counting TUNEL-positive cells in the hippocampus of mice exposed to isoflurane or oxygen treatment. Isoflurane significantly increased the number of TUNEL-positive cells in wild type mice compared to the wild control group (Figure 4). However, loss of either FAS or FASL occluded this isoflurane-dependent cell death in the hippocampus (Figures 4(a) and 4(b)). FAS/FASL-gene-knockout mice showed fewer apoptosis cells in hippocampus no matter whether they were in pure oxygen group or isoflurane group compared to wild isoflurane group.

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