Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period

Abstract

BackgroundMounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR.MethodsWistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2–21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-κB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17 of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation.ResultsMS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-κB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-κB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF-κB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia.ConclusionsEarly life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses.

Cistanches alleviates sevoflurane‐induced cognitive dysfunction by regulating PPAR‐γ‐dependent antioxidant and anti‐inflammatory in rats

“…2, 28 Gong has described that sevoflurane exposure impaired spatial memory in aged rats by increasing inflammation. 30 On the other hand, the elevated antioxidant defence and apoptosis status were also observed in blood samples of sevoflurane-administered children. 30 On the other hand, the elevated antioxidant defence and apoptosis status were also observed in blood samples of sevoflurane-administered children.…”

Potential neurotoxicity of prenatal exposure to sevoflurane on offspring: Metabolomics investigation on neurodevelopment and underlying mechanism

“…Since DNA methylation shows functions because of its ability of regulating genes expression (Bansal and Pinney, 2017), neurological diseases-related DNA hypomethylation or hypermethylation may be the results of the alteration of functional biomolecules mediated by some altered certain genes expression. Zhu Y et al reported that hypermethylation of a certain DNA promoter up-regulated neuroinflammation after sevoflurane anesthesia in animal-model of endoplasmic reticulum stress occurred during the neonatal period (Zhu et al, 2017). Although no proof associated with hypomethylation of DNA, it gives some support for the viewpoint of DNA hypermethylation in neurological damage after sevoflurane anesthesia at least in part.…”

“…In this study, presence of leukotriene E4 might hint that prenatal exposure to sevoflurane caused neuroinflammation in offspring. Meanwhile, since inflammatory genes were regulated by methylation in neurodegenerative diseases (Nicolia et al, 2017), it was plausible that methylation served as a crucial role between neuroinflammation and neurotoxicity, and this assumption has been partially confirmed (Zhu et al, 2017).…”

Association of global DNA hypomethylation with post‐operative cognitive dysfunction in elderly patients undergoing hip surgery

“…In the brain, DNA methylation is essential for regulating synaptic plasticity in hippocampal neurons, thereby influencing learning and memory . Furthermore, epigenetic mechanisms strongly influence the regulation of neuroinflammation, which underlies the development of POCD . However, data in support of an association between global DNA methylation and changes in cognitive function in patients with POCD are not available.…”