DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats

Abstract

DNA methylation is an essential epigenetic mechanism involving in gene transcription modulation. An age-related increase in promoter methylation has been observed for neuronal activity and memory genes, and participates in neurological disorders. However, the position and precise mechanism of DNA methylation for memory gene modulation in anesthesia related cognitive impairment remained to be determined. Here, we studied the effects of sevoflurane anesthesia on the transcription of memory genes in the aged rat hippocampus. Then, we investigated changes in DNA methylation of involved genes and verified whether dysregulated DNA methylation would contribute to anesthesia induced cognitive impairment. The results indicated that sevoflurane anesthesia down-regulated the mRNA and protein levels of three memory genes, Arc, Bdnf, and Reln, which were accompanied with promoter hypermethylation and increased Dnmt1, Dnmt3a, and Mecp2 expression, and finally impaired hippocampus dependent memory. Furthermore, inhibition of DNA hypermethylation by 5-Aza rescued sevoflurane induced memory gene expression decrease and cognitive impairment. These findings provide an epigenetic understanding for the pathophysiology of cognitive impairment induced by general anesthesia in aged brain.

TRPV1 Antagonist Prevents Neonatal Sevoflurane-Induced Synaptic Abnormality and Cognitive Impairment in Mice Through Regulating the Src/Cofilin Signaling Pathway

“…Because the contextual fear conditioning was the hippocampal dependent learning, and tone fear conditioning was hippocampal independent learning ( Phillips and LeDoux, 1992 ; Medina et al, 2002 ). It is possible that the amygdala function was unlikely impaired and the expression of TRPV1 in the amygdala remained unchanged, thus sevoflurane did not induce memory impairment which was consistent with the previous studies ( Ni et al, 2020 ; Wang et al, 2020 ).…”

A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice

“… 9 , 38 Indeed, studies on PND have also observed global DNA hypomethylation, 11 , 39 and DNA hypermethylation of several genes (e.g. glucocorticoid receptor, Arc, Bdnf, Reln, PSD‐95 ), 10 , 40 , 41 indicating that the global DNA methylation status did not necessarily reflect the methylation of specific genes. More importantly, we found that SAM could function as a “hypomethylating” agent to hypomethylate the NR2B gene, supporting that SAM is a methylome modulator rather than a pure “hypermethylating” agent as it used to be predicted.…”

“…transcription factors) 8 . An imbalance of DNA methylation has been regarded as a valuable biomarker for aging and aging‐related pathologies, including PND 9–11 . Importantly, previous studies have reported that methylation at specific CpG sites around the promoter of NR2B gene will downregulate NR2B transcription 12,13 .…”

“… 8 An imbalance of DNA methylation has been regarded as a valuable biomarker for aging and aging‐related pathologies, including PND. 9 , 10 , 11 Importantly, previous studies have reported that methylation at specific CpG sites around the promoter of NR2B gene will downregulate NR2B transcription. 12 , 13 However, whether DNA methylation is involved in the regulation of NR2B by laparotomy and the associated cellular mechanism is still unknown.…”

A National Population Cohort Study Showed That Exposure to General Anesthesia in Early Childhood Is Associated with an Increase in the Risk of Developmental Delay

“…These pre-clinical literatures have shown changes in neuronal apoptosis that may lead to post-anesthesia cognitive dysfunction [8][9][10]. In addition, sevoflurane can also manipulate memory genes and induce cognitive impairment in aged rodents [11]. More importantly, whether these biological findings of neuronal damage in animal studies will occur in children has become an important issue in the daily anesthesia practice of children.…”