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KMID : 1034820210170030287
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Molecular & Cellular Toxicology
2021 Volume.17 No. 3 p.287 ~ p.295
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Sevoflurane induces neuronal apoptosis via enhancing DNMT3L expression and promoting methylation of PSD95 promoter in postoperative cognitive dysfunction
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Ling Yunzhi
Li Xiaohong
Yu Li
Sun Yiyun
Yang Dongdong
Li Zhiyi
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Abstract
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Background: Postoperative cognitive dysfunction (POCD) is a central nervous system (CNS) complication and occurs quite frequently after anesthesia, especially in elderly patients. DNA (cytosine-5)-methyltransferase 3-like (DNMT3L) is an enzymatically inactive regulatory factor that can modulate gene expression via methylation. Few studies specifically focused on the role of DNMT3L in sevoflurane-induced POCD.
Objective: The cognitive dysfunction was determined by Morris water maze assay. Hippocampal neuron apoptosis was measured by TdT-mediated dUTP nick-end labeling (TUNEL) assay. Neuron proliferation and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry assay. The expression levels of DNMT3L and postsynaptic density protein-95 (PSD95) were measured by qRT-PCR and western blot.
Results: The sevoflurane-induced POCD aging rat model was established for in vivo study. Suppression of DNA methylation by 5-Aza-2′-deoxycytidine (5-AZA; a widely used methylation inhibitor) reversed sevoflurane-induced cognitive dysfunction and hippocampal neuron apoptosis in rats. Moreover, sevoflurane enhanced DNMT3L expression and induced methylation of PSD95 promoter in vivo. In vitro, sevoflurane induced neuronal apoptosis and DNMT3L expression to promote PSD95 methylation. Finally, rescue experiments indicated that sevoflurane induced neuron apoptosis by increasing DNMT3L expression and promoting methylation of PDS95 in POCD.
Conclusion: Sevoflurane induced neuronal apoptosis by increasing DNMT3L expression and promoting methylation of PDS95 in vivo and in vitro, providing a novel therapeutic strategy for POCD.
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KEYWORD
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Sevoflurane, Neuronal apoptosis, DNMT3L, Methylation, PSD95, Postoperative cognitive dysfunction
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