Characterization of DNA hydroxymethylation in the hypothalamus of elderly mice with post‑operative cognitive dysfunction

Abstract

Post-operative cognitive dysfunction (POCD) is a common syndrome characterized by perioperative cerebral damage in elderly patients, including cognitive impairment and memory loss. Recent studies have revealed that anesthesia is one of the key causes of POCD. Ubiquitin-like with PHD and ring finger domains 2 (Uhrf2) has been reported to play a crucial role in regulating DNA methylation and hydroxymethylation, which are closely connected with memory building and erasure. However, whether narcotic drugs can affect Uhrf2 to impact on DNA methylation and hydroxymethylation in POCD is poorly understood. In this study, a POCD model was established in elderly mice through sevoflurane treatment, and these mice were found to have compromised levels of global DNA 5′-hydroxymethylcytosine (5hmC) and Uhrf2 in the hippocampus and the amygdaloid nucleus, when compared with non-POCD and control mice. The results of immunoprecipitation and quantitative PCR revealed that 5hmC modification of the promoters of genes associated with neural protection and development, such as glial cell-derived neurotrophic factor, brain derived neurotrophic factor, glucocorticoid receptor and acyl-CoA sythetase short chain family member 2, was reduced in the hippocampus of POCD mice when compared with non-POCD and control mice. Taken together, the findings of the present study suggest that loss of 5hmC, in the hippocampus and the amygdaloid nucleus modulated by Uhrf2 suppression, may result in the learning and memory ability impairment seen in mice with POCD.

Microarray Analysis Identifies Key Differentially Expressed Circular RNAs in Aged Mice With Postoperative Cognitive Dysfunction

“…In the GO analyses, the top three terms of the upregulated genes were identical protein binding, extracellular region, and tube morphogenesis; for downregulated genes, the top three terms were protein binding, cell part, and localization. Next, KEGG pathway analysis showed that the upregulated genes included adherens junction, phospholipase D, ErbB signaling pathway, and the downregulated genes involved in the MAPK signaling pathway and mediated proteolysis, which were revealed to be associated with POCD (Li et al, 2014(Li et al, , 2016Vutskits and Xie, 2016;Zhang et al, 2016;Ding et al, 2017;Lu et al, 2017;Wang D. S. et al, 2018;Wang W. X. et al, 2018;Orser and Wang, 2019;Zheng et al, 2019;Zhong and Xu, 2019). Thus, these bioinformatics analyses of possible pathways also suggested the potential functions of the identified circRNAs in POCD of aged mice.…”

“…The pathogenesis of POCD is complex and lacks effective diagnosis and treatment. Therefore, several recent studies have focused on the epigenetic regulation of the pathogenesis of POCD to discover potential therapies (Li et al, 2015;Liu et al, 2019;Zhong and Xu, 2019). miRNAs and lncRNAs in the brain have been reported to contribute to POCD Su et al, 2019).…”

METTL3 regulates hippocampal gene transcription via N6-methyladenosine methylation in sevoflurane-induced postoperative cognitive dysfunction mouse

“…A POCD mouse model was established as previously described [ 10 , 11 ]. In brief, fifty 40-week-old outbred female C57BL/6 mice purchased from the experimental animal center of Xiangnan University were enrolled in this study.…”

“…The general inhaled anesthetics such as sevoflurane can increase the risk of Alzheimer's disease (AD) in the aging brain [ 6 ] and exert neurotoxic effects through neuroinflammation [ 7 ], caspase-mediated apoptosis [ 8 ], mitochondrial dysfunction, and oxidative stress [ 9 ]. Recently, sevoflurane has been utilized to establish a POCD rodent model to explore the underlying mechanism of POCD’s pathogenesis [ 10 , 11 ], indicating that sevoflurane is implicated in the causation of the neurological and cognitive deficits seen in POCD.…”

Intergenerational Perioperative Neurocognitive Disorder

“…Animal studies with SEVO and isoflurane support the possibility that GAs themselves may induce DNA methylation changes in the brain and neurobehavioral deficiencies. In one such study, 18-month-old mice were exposed to 2% SEVO for 2 h [ 313 ]. The animals’ behavior was evaluated until day 7 after exposure to SEVO, followed by the collection of brain tissue.…”