Dataset Information

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

ABSTRACT:

Aims

This study was designed to investigate the role of NR2B and the contribution of DNA methylation to NR2B expression in the pathogenesis of PND.

Methods

Eighteen-month-old C57BL/6J mice were subjected to experimental laparotomy under 1.4% isoflurane anesthesia. Hippocampus-dependent learning and memory were evaluated by using the Barnes maze and contextual fear conditioning tests. The protein and mRNA expression levels of NR2B were evaluated by western blotting and qRT-PCR respectively, and the methylation of the NR2B gene was examined by using targeted bisulfite sequencing. Long-term synaptic plasticity (LTP) was measured by electrophysiology.

Results

Mice that underwent laparotomy exhibited hippocampus-dependent cognitive deficits accompanied by decreased NR2B expressions and LTP deficiency. The overexpression of NR2B in the dorsal hippocampus could improve learning and memory in mice subjected to laparotomy. In particular, the decreased NR2B expressions induced by laparotomy was attributed to the NR2B gene hypermethylation. Preoperative administration of S-adenosylmethionine (SAM) could hypomethylate the NR2B gene, upregulate NR2B expression and improve LTP, exerting a dose-dependent therapeutic effect against PND. Moreover, inhibiting NR2B abrogated the benefits of SAM pretreatment.

Conclusions

Laparotomy cause hippocampus-dependent cognitive decline by hypermethylating the NR2B gene, allowing us to understand the pathogenesis of PND in an epigenetic landscape.

SUBMITTER: Xu F

PROVIDER: S-EPMC10068472 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

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

Xu Feifei F Cong Peilin P Zhang Bingqian B Dong Hailong H Zuo Wenqiang W Wu Tingmei T Tian Li L Xiong Lize L

CNS neuroscience & therapeutics 20230124 5

<h4>Aims</h4>This study was designed to investigate the role of NR2B and the contribution of DNA methylation to NR2B expression in the pathogenesis of PND.<h4>Methods</h4>Eighteen-month-old C57BL/6J mice were subjected to experimental laparotomy under 1.4% isoflurane anesthesia. Hippocampus-dependent learning and memory were evaluated by using the Barnes maze and contextual fear conditioning tests. The protein and mRNA expression levels of NR2B were evaluated by western blotting and qRT-PCR resp ...[more]

PMID: 36694341

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Project description:BackgroundPerioperative neurocognitive disorder (PND) is a long-term postoperative complication in elderly surgical patients. The underlying mechanism of PND is unclear, and no effective therapies are currently available. It is believed that neuroinflammation plays an important role in triggering PND. The secreted glycoprotein myeloid differentiation factor 2 (MD2) functions as an activator of the Toll-like receptor 4 (TLR4) inflammatory pathway, and α5GABAA receptors (α5GABAARs) are known to play a key role in regulating inflammation-induced cognitive deficits. Thus, in this study, we aimed to investigate the role of MD2 in PND and determine whether α5GABAARs are involved in the function of MD2.MethodsEighteen-month-old C57BL/6J mice were subjected to laparotomy under isoflurane anesthesia to induce PND. The Barnes maze was used to assess spatial reference learning and memory, and the expression of hippocampal MD2 was assayed by western blotting. MD2 expression was downregulated by bilateral injection of AAV-shMD2 into the hippocampus or tail vein injection of the synthetic MD2 degrading peptide Tat-CIRP-CMA (TCM) to evaluate the effect of MD2. Primary cultured neurons from brain tissue block containing cortices and hippocampus were treated with Tat-CIRP-CMA to investigate whether downregulating MD2 expression affected the expression of α5GABAARs. Electrophysiology was employed to measure tonic currents. For α5GABAARs intervention experiments, L-655,708 and L-838,417 were used to inhibit or activate α5GABAARs, respectively.ResultsSurgery under inhaled isoflurane anesthesia induced cognitive impairments and elevated the expression of MD2 in the hippocampus. Downregulation of MD2 expression by AAV-shMD2 or Tat-CIRP-CMA improved the spatial reference learning and memory in animals subjected to anesthesia and surgery. Furthermore, Tat-CIRP-CMA treatment decreased the expression of membrane α5GABAARs and tonic currents in CA1 pyramidal neurons in the hippocampus. Inhibition of α5GABAARs by L-655,708 alleviated cognitive impairments after anesthesia and surgery. More importantly, activation of α5GABAARs by L-838,417 abrogated the protective effects of Tat-CIRP-CMA against anesthesia and surgery-induced spatial reference learning and memory deficits.ConclusionsMD2 contributes to the occurrence of PND by regulating α5GABAARs in aged mice, and Tat-CIRP-CMA is a promising neuroprotectant against PND.

Project description:BackgroundPerioperative neurocognitive disorders (PND) occur frequently after surgery, especially in aged patients. Surgery-induced neuroinflammation and blood-brain barrier (BBB) dysfunction play a crucial role in the pathogenesis of PND. Interleukin-17A (IL-17A) increases after surgical stress and will be involved in BBB dysfunction. However, the effect of IL-17A on BBB function during PND remains poorly understood.MethodsMale wild-type C57BL/6J mice (15 months old) received tibial fracture surgery and fixation to establish the PND model. All the mice were injected intraperitoneally with an IL-17A-neutralizing antibody (Abs) or isotype-control Abs 30 min before tibial fracture surgery. Animal behaviour tests conducted 24 h after surgery included the contextual fear conditioning and Y maze tests. Serum and hippocampus IL-17A levels and hippocampus IL-6 and IL-1β levels were detected by ELISA. BBB function was detected by Evans blue (EB) test. Hippocampus matrix metalloproteinase-2 (MMP-2)- and MMP-9-positive cells were detected by immunohistochemistry. Hippocampus albumin, occludin, claudin-5 and IL-17A receptors were detected by Western blot. For the in vitro experiment, bEnd.3 cells were incubated with IL-17A. Cell IL-17A receptors were detected by immunofluorescence. Cellular MMP-2, MMP-9, occludin, and claudin-5 were detected by Western blot.ResultsTibial fracture surgery promoted memory impairment, increased levels of IL-17A and IL-17A receptors, inflammatory factor production and BBB dysfunction. IL-17A Abs inhibited this effect, including improving memory function, decreasing inflammatory factor production and alleviating BBB disruption, indicated by decreased tight junctions (TJs) and increased MMPs after surgery. The in vitro study suggested that recombinant IL-17A could upregulate the expression of IL-17A receptors, decrease TJs and increase the level of MMPs in bEnd.3 cells.ConclusionsOur results suggested that IL-17A-promoted BBB disruption might play an important role in the pathogenesis of PND.

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Project description:BackgroundPerioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.MethodshUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in eighteen-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, systemic and neuroinflammatory responses, neuroplasticity, endogenous neurogenesis, and brain-derived neurotrophic factor (BDNF) were assessed. To determine the brain mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.ResultshUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of systemic and hippocampal inflammation and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.ConclusionsOur study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

Dataset Information

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

Aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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