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Sevoflurane induces neuronal apoptosis via enhancing DNMT3L expression and promoting methylation of PSD95 promoter in postoperative cognitive dysfunction
Molecular & Cellular Toxicology  (IF1.08),  Pub Date : 2021-05-05, DOI: 10.1007/s13273-021-00135-8
Yunzhi Ling, Xiaohong Li, Li Yu, Yiyun Sun, Dongdong Yang, Zhiyi Li

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.