Abstract
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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This work was supported by Natural Science Research Project of Anhui Educational Committee (Grant No. KJ2019A0330).
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YL and XL designed the study, supervised data collection, LY analyzed the data, interpreted the data, YS, DY and ZL prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.
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Yunzhi Ling states that there are no conflicts of interest to disclose. Xiaohong Li states that there are no conflicts of interest to disclose. Li Yu states that there are no conflicts of interest to disclose. Yiyun Sun states that there are no conflicts of interest to disclose. Dongdong Yang states that there are no conflicts of interest to disclose. Zhiyi Li states that there are no conflicts of interest to disclose.
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All animal experiments were approved by the Experimental Animal Management and Ethics Committee of Bengbu Medical College for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.
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Ling, Y., Li, X., Yu, L. et al. Sevoflurane induces neuronal apoptosis via enhancing DNMT3L expression and promoting methylation of PSD95 promoter in postoperative cognitive dysfunction. Mol. Cell. Toxicol. 17, 287–295 (2021). https://doi.org/10.1007/s13273-021-00135-8
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DOI: https://doi.org/10.1007/s13273-021-00135-8