A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

[Genetic basis of postoperative cognitive dysfunction]. / Geneticheskie osnovy postoperatsionnoi kognitivnoi disfunktsii.

This review highlights literature data on potential genetic markers that potentially influence the development of postoperative cognitive dysfunction, such as TOMM40, APOE, TREM2, METTL3, PGC1a, HMGB1 and ERMN. The main pathogenetic mechanisms triggered by these genes and leading to the development of cognitive impairment after anesthesia are described. The paper systematizes previously published works that provide evidence of the impact of specific genetic variants on the development of postoperative cognitive dysfunction.

CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer's diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Sirtuin 3 (SIRT3) improves sevoflurane-induced postoperative cognitive impairment by regulating mitochondrial oxidative stress.

One of the most prevalent co-operative disorders is postoperative cognitive dysfunction (POCD), however, its pathogenesis remains unclear. Thus, the aim of this work was to evaluate SIRT3's impact on cognitive decline in aged mice under anesthesia. Adeno-associated virus SIRT3 vector (AAV-SIRT3) or empty vector (AAV-VEH) was injected into the hippocampal region of aged mice after sevoflurane induction in order to upregulate the expression of SIRT3. The expression levels of SIRT3, pro-inflammatory cytokines, and apoptotic factors in hippocampus tissues were identified by PCR, Western blotting, TUNEL staining, and enzyme-linked immunosorbent assay (ELISA), and the cognitive function of mice was assessed. The SIRT3 expression was down-regulated in the hippocampal tissue of anesthetized mice. SIRT3 overexpression can improve the learning and memory ability, reduce the escape latency, and increase the residence time in the platform and platform crossing ability of mice. The overexpression of SIRT3 in hippocampus can reduce the oxidative stress response and inflammatory response induced by anesthesia in mice, increase the superoxide dismutase (SOD) expression level, and decrease the expression level of MDA and inflammatory factors in hippocampus. In addition, SIRT3 overexpression can also reduce anesthetic-induced hippocampal cell apoptosis. By reducing the hippocampus mitochondrial oxidative stress response, SIRT3 plays a significant role in the pathophysiology of POCD in mice and is a potential target for POCD treatment and diagnosis.

Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of POCD. In addition, SMAD family member 7 (Smad7) has been confirmed to play vital roles in the pathogenesis and treatment of inflammatory diseases, such as inflammatory bowel disease. However, whether Smad7 participates in the regulatory process of neuroinflammation and apoptosis in the development of POCD is still unknown. METHODS: In this study, a POCD mouse model was constructed by unilateral nephrectomy under anesthesia, and cognitive function was assessed using the fear conditioning test and open field test. The expression of Smad7 at the mRNA and protein levels in the hippocampus 3 days after surgery was examined by qRT-PCR, western blot and immunofluorescence assays. Furthermore, to identify whether the elevation of Smad7 in the hippocampus after unilateral nephrectomy contributes to cognitive impairment, the expression of Smad7 in the hippocampal CA1 region was downregulated by crossing Smad7fl/fl conditional mutant mice and CaMKIIα-Cre line T29-1 transgenic mice or stereotaxic injection of shRNA-Smad7. Inflammation and apoptosis in the hippocampus were assessed by measuring the mRNA levels of typical inflammatory cytokines, including TNF-α, IL-1ß, IL-6, CCL2, CXCL1, and CXCL2, and the protein levels of apoptotic proteins, including Bax and Bcl2. In addition, apoptosis in the hippocampus postoperation was investigated by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay. Finally, western blotting was used to explore how Smad7 mediates inflammation and apoptosis postoperation. RESULTS: The results unequivocally revealed that elevated Smad7 in the hippocampal CA1 region significantly inhibited TGF-ß signal transduction by blocking Smad2/3 phosphorylation, which enhanced neuroinflammation and apoptosis in the hippocampus and further led to learning and memory impairment after surgery. CONCLUSIONS: Our results revealed that Smad7 contributes to cognitive impairment after surgery by enhancing neuroinflammation and apoptosis in the hippocampus and might serve as a promising therapeutic target for the treatment of memory impairment after anesthesia surgery.

M1-Type Microglia-Derived Extracellular Vesicles Overexpressing IL-1R1 Promote Postoperative Cognitive Dysfunction by Regulating Neuronal Inflammation.

Postoperative cognitive dysfunction (POCD) is a common complication after surgical anesthesia, mainly manifested as memory impairment, decreased attention, and cognitive function with mood and personality changes. Activated microglia (M1-type microglia) have been demonstrated to release inflammatory substances (IL-1ß, TNF-α, etc.) that cause neuronal degeneration and death by activating the NF-κB signaling pathway and upregulating Caspase-3 and Bax. However, the pathogenesis of POCD is still not fully understood and needs further research. In the present study, we investigated the effect of M1-type microglia-derived extracellular vesicles (EVsM1-Microglia) in the pathological process of POCD. The levels of NF-κB phosphorylation and IL-1ß protein expression in hippocampal neurons were significantly increased in the Surgery group, while PSD95 and MAP2 were significantly decreased. Surgery induced microglia activation, synapse-associated protein decrease, and neuronal degeneration in hippocampus. And the amount of spine and mushroom spine significantly decreased in surgical mice, which was reverted in the presence of IL-1R1 siRNA. In addition, EVsM1-Microglia promoted synaptic loss and neuron degeneration independent of surgery and microglia activation. Furthermore, EVsM1-Microglia promoted memory defects in surgical mice. We demonstrated that EVsM1-Microglia with high expression of IL-1R1 promote POCD development by regulating neuronal inflammation.

The role of epigenetic modification in postoperative cognitive dysfunction.

With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.

Microglial priming induced by loss of Mef2C contributes to postoperative cognitive dysfunction in aged mice.

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system (CNS) complication with a higher occurrence among aged individuals than among young individuals. The aim of this study was to explore the mechanisms by which POCD preferentially affects older individuals. We found here that exploratory laparotomy induced cognitive function decline in aged mice but not in young mice and that this decline was accompanied by inflammatory activation of microglia in the hippocampus. Furthermore, microglial depletion by feeding of a standard diet containing a colony stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) markedly protected aged mice from POCD. Notably, the expression of myocyte-specific enhancer 2C (Mef2C), an immune checkpoint that limits overactivation of microglia, was downregulated in aged microglia. Knocking down Mef2C induced a microglial priming phenotype in young mice, resulting in postoperative increases in the hippocampal levels of the inflammatory factors IL1-ß, IL-6 and TNF-α that could impair cognition; these findings were consistent with the observations in aged mice. In vitro, BV2 cells lacking Mef2C released higher levels of inflammatory cytokines upon stimulation with lipopolysaccharide (LPS, a bacterial toxin) than Mef2C-sufficient cells. Moreover, upregulation of Mef2C in aged mice restrained postoperative microglial activation, attenuating the neuroinflammatory response and cognitive impairment. These results reveal that during aging, loss of Mef2C leads to microglial priming, amplifying postsurgical neuroinflammation and contributing to the vulnerability of elderly patients to POCD. Thus, targeting the immune checkpoint Mef2C in microglia may be a potential strategy for the prevention and treatment of POCD in aged individuals.

FGF19 improves sevoflurane-induced cognitive dysfunction in rats through the PGC-1α/BDNF/FNDC5 pathway.

Postoperative cognitive dysfunction (POCD) is a serious central nervous system complication characterized by impaired memory, reduced information processing ability, and anxiety. Recently, the role of FGF19 in neurological diseases has been reported. However, the effect and mechanisms of FGF19 in improving symptoms of POCD remain unknown. This study aimed to identify the role and exploring the underlying mechanisms of FGF19 in POCD. Here, rats were separated into four different groups, including control, sevoflurane (sev), sev + AAV-empty, and sev + AAV-FGF19 group. Then, the Morris water maze (MWM) test was applied to identify the effect of FGF19 on POCD rats. The result proved that FGF19 improved sevoflurane induced cognitive dysfunction in rats. Subsequently, the expressions of TNF-α, IL-6, IL-1ß, and IL-10 were detected to verify the anti-neuroinflammatory effects of FGF19 in POCD rats. Furthermore, DHE fluorescent staining assay showed that FGF19 could inhibit sevoflurane-induced oxidative stress in POCD rats. Besides, NISSL staining and TUNEL assay were applied to reveal that FGF19 could alleviate hippocampal neuron injury induced by sevoflurane in rats. Moreover, mechanistic studies confirmed that FGF19 improved symptoms of POCD by mediated PGC-1α/BDNF/FNDC5 pathway. Together, these results suggested that FGF19 improves sevoflurane-induced POCD in rats through the PGC-1α/BDNF/FNDC5 pathway.

SIRT3 Enhances the Protective Role of Propofol in Postoperative Cognitive Dysfunction via Activating Autophagy Mediated by AMPK/mTOR Pathway.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery and anesthesia. In this study, we aimed to determine the neuroprotective mechanism of Sirtuin 3 (SIRT3) and propofol in POCD. METHODS: The cognitive dysfunction models in C57BL/6J mice were induced and treated, then cognitive function of mice were tested using morris water maze and novel object recognition tests. Primary neurons were stimulated by lipopolysaccharide (LPS) to mimic neuroinflammation during POCD. Meanwhile, cells were treated with propofol. 3-methyladenine (3-MA) was administrated to inhibit autophagy in neurons. SIRT3 overexpression vector was constructed to upregulate SIRT3. Biomarker changes in inflammation, oxidative stress and autophagy were determined in vivo and in vitro. RESULTS: Propofol enhanced the spatial cognitive ability and novel objective recognition of POCD mice. Inflammation and oxidative stress were observed in the hippocampus, which were inhibited by propofol treatment. During POCD, SIRT3 expression and autophagy in the hippocampus was decreased; propofol activated autophagy and upregulated SIRT3. In LPS-stimulated neurons, SIRT3 upregulation enhanced the anti-inflammation and anti-oxidative stress roles of propofol; SIRT3 elevated propofol-activated autophagy in neurons undergoing LPS administration. Moreover, 3-MA reversed propofol-induced biomarker changes in inflammation, oxidative stress and autophagy in LPS-stimulated neurons. In POCD mice, SIRT3 upregulation enhanced the cognitive function during propofol treatment; SIRT3 overexpression elevated the inhibitory role of propofol in inflammation, oxidative stress and autophagy. AMPK/mTOR pathway was activated in response to propofol treatment and SIRT3 enhanced the signaling activation. CONCLUSIONS: SIRT3 enhances the protective effect of propofol on POCD by triggering autophagy that eliminates oxidative stress and inhibits the production of pro-inflammatory cytokines.

Epigenetic Mechanisms of Postoperative Cognitive Impairment Induced by Anesthesia and Neuroinflammation.

Cognitive impairment after surgery is a common problem, affects mainly the elderly, and can be divided into postoperative delirium and postoperative cognitive dysfunction. Both phenomena are accompanied by neuroinflammation; however, the precise molecular mechanisms underlying cognitive impairment after anesthesia are not yet fully understood. Anesthesiological drugs can have a longer-term influence on protein transcription, thus, epigenetics is a possible mechanism that impacts on cognitive function. Epigenetic mechanisms may be responsible for long-lasting effects and may implicate novel therapeutic approaches. Hence, we here summarize the existing literature connecting postoperative cognitive impairment to anesthesia. It becomes clear that anesthetics alter the expression of DNA and histone modifying enzymes, which, in turn, affect epigenetic markers, such as methylation, histone acetylation and histone methylation on inflammatory genes (e.g., TNF-alpha, IL-6 or IL1 beta) and genes which are responsible for neuronal development (such as brain-derived neurotrophic factor). Neuroinflammation is generally increased after anesthesia and neuronal growth decreased. All these changes can induce cognitive impairment. The inhibition of histone deacetylase especially alleviates cognitive impairment after surgery and might be a novel therapeutic option for treatment. However, further research with human subjects is necessary because most findings are from animal models.

Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery.

BACKGROUND: Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer's disease [AD]). METHODS: In a nested matched case-control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of 1305 plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). RESULTS: We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2-5.0] and 2.1[1.1-4.1], respectively). CONCLUSIONS: Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults.

Effects of LncRNA GAS5/miR-137 general anesthesia on cognitive function by TCF4 inflammatory bodies in patients undergoing lumbar spinal canal decompression.

Lumbar spinal stenosis is a common orthopedic disease in clinical practice at present. Postoperative cognitive dysfunction (POCD) refers to the phenomenon of impaired memory. However, whether long noncoding RNA (LncRNA) GAS5 contributes to the mechanism of cognitive function in undergoing lumbar spinal canal decompression remains unknown. Thus, the present study investigated the precise details of LncRNA GAS5 involvement in Postoperative cognitive dysfunction of patients undergoing lumbar spinal canal decompression. Patients undergoing lumbar spinal canal decompression with cognitive function and Normal healthy volunteers were obtained. C57BL/6 mice were maintained with a 2% concentration of sevoflurane in 100% oxygen at a flow rate of 2 L minute-1 for 4 hours. LncRNA GAS5 gene expression were up-regulated in patients undergoing lumbar spinal canal decompression. In mice model, LncRNA GAS5 gene expression also increased. LncRNA GAS5 promoted neuroinflammation in vitro model. LncRNA GAS5 raised cognitive impairment and increased neuroinflammation in mice model. LncRNA GAS5 suppressed miR-137 in vitro model. MiR-137 reduced neuroinflammation in vitro model. MiR-137 suppressed TCF4 protein expression in vitro model. Transcription factor TCF4 activates the expression of bHLH. Taking together, this experiment provide the first experimental and clinical evidence that LncRNA GAS5/miR-137 promoted anesthesia-induced cognitive function to increase inflammatory bodies in patients undergoing lumbar spinal canal decompression, suggesting it may be a biomarker of POCD and a potential therapeutic target for POCD.

Minor allele of rs55763075 located in MTHFR is associated with the risk of cognitive impairment after anesthesia via modulating miR-34b.

This study aimed to investigate the association between cognitive impairment after general anesthesia and rs55763075 polymorphisms. We enrolled and grouped patients undergoing general anesthesia according to their genotypes of rs55763075 polymorphism. Mini-Mental State Examination (MMSE) scoring was performed to evaluate the cognitive status of patients. Quantitative real-time PCR was carried out to analyze the expression of methylenetetrahydrofolate reductase (MTHFR) mRNA and miR-34b while Western blot was performed to evaluate the expression of MTHFR protein. Furthermore, we studied the effect of rs55763075 polymorphism on the expression of MEHFR via luciferase assay. Accordingly, we found that the MMSE score in GG/GA groups was significantly higher than that in AA group. And a significant reduction of MTHFR mRNA expression was observed in the serum and peripheral blood mononuclear cells (PBMCs) of patients carrying AA genotype compared with the patients carrying GG/GA genotypes. Moreover, the MTHFR expression was much lower in the cultured AA-genotyped cells transfected with miR-34b. Luciferase assay results also showed that miR-34b transfection reduced luciferase activity in the cells carrying A allele but not in cells carrying G allele. In summary, the data of this study showed that minor allele (A) of rs55763075 polymorphisms in the 3'-untranslated region of MTHFR mRNA generated a potential binding site for miR-34b, which led to reduced level of folic acid in the patients carrying the AA genotype. Furthermore, we found that the MMSE score of AA-genotyped patients was lower than that of patients carrying GG/GA genotypes.

LncRNA NONMMUT055714 acts as the sponge of microRNA-7684-5p to protect against postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a neurological complication of surgery especially common in elderly patients. In this study, we investigated the role of NONMMUT055714 in POCD via regulation of miR-7684-5p. In a POCD mouse model, we induced overexpression of NONMUTT055714 via transfection of lentivrus into the hippocampus, and used the Morris water maze for assessment of cognitive function. Silencing of NONMUTT055714 and miR-7684-5p was induced in primary hippocampal neurons to observe the effects of these regulatory RNAs on cellular processes. Bioinformatics analysis and a double luciferase reporter experiment were performed to further explore the relationship between NONMMUT055714, miR-7684-5p, and SORLA. Cell and animal rescue experiments were performed to verify the ability of miR-7684-5p to reverse the protective effects of NONMMUT055714 overexpression in POCD. We observed that NONMMUT055714 has decreased expression in the POCD mouse model. Overexpression of NONMMUT055714 protected against cognitive impairment of the POCD mouse model in vivo. We identified miR-7684-5p as a NONMMUT055714-related miRNA and in turn as an upstream regulator of SORLA. We found that NONMMUT055714 downregulation is associated with decreased SORLA, increased Aß and p-tau expression, increased inflammatory biomarkers, increased markers of oxidative stress, and increased neuronal apoptosis in vitro. The effects of NONMMUT055714 downregulation were reversed by silencing miR-7684-5p in vitro and in vivo. Taken together, our findings suggest that NONMMUT055714 is protective against the development of POCD via its function as a ceRNA (or miRNA sponge) in the regulation of miR-7684-5p and SORLA. We therefore propose NONMMUT055714 as a novel target for the investigation and prevention of POCD.

LncRNA Rian ameliorates sevoflurane anesthesia-induced cognitive dysfunction through regulation of miR-143-3p/LIMK1 axis.

Sevoflurane could stimulate neurotoxicity and result in postoperative cognitive dysfunction (POCD). Long non-coding RNAs (lncRNAs) have been implicated in the regulation of nervous system disease. This study was performed to investigate role and mechanism of lncRNA Rian (RNA imprinted and accumulated in nucleus) in sevoflurane anesthesia-induced cognitive dysfunction. Mice post-sevoflurane anesthesia showed cognitive impairments and neuronal damage and apoptosis. However, intracerebroventricularly injection with Adenovirus (Ad) for the over-expression of Rian ameliorated sevoflurane-induced neuronal damage and apoptosis. Cognitive impairments induced by sevoflurane were attenuated by injection with Ad-Rian. Moreover, transfection with Ad-Rian also protected isolated primary hippocampal neurons against sevoflurane-induced decrease of cell viability and increase of lactic acid dehydrogenase (LDH) and apoptosis. Mechanistically, Rian bind to miR-143-3p, and decreased expression of LIMK1 (Lim kinase 1) through negative regulation of miR-143-3p. Knockdown of LIMK1 aggravated sevoflurane-induced decrease of cell viability and increase of LDH and apoptosis in neurons, while over-expression attenuated LIMK1 silence-induced neuronal damage post-sevoflurane anesthesia. In conclusion, Rian demonstrated neuroprotective effects against sevoflurane anesthesia-induced cognitive dysfunction through regulation of miR-143-3p/LIMK1 axis, providing promising target for sevoflurane anesthesia-induced cognitive dysfunction.

Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats.

Postoperative cognitive dysfunction (POCD) is the collection of cognitive impairments, lasting days to months, experienced by individuals following surgery. Persistent POCD is most commonly experienced by older individuals and is associated with a greater vulnerability to developing Alzheimer's disease, but the underlying mechanisms are not known. It is known that laparotomy (exploratory abdominal surgery) in aged rats produces memory impairments for 4 days. Here we report that postsurgical treatment with morphine extends this deficit to at least 2 months while having no effects in the absence of surgery. Indeed, hippocampal-dependent long-term memory was impaired 2, 4, and 8 weeks postsurgery only in aged, morphine-treated rats. Short-term memory remained intact. Morphine is known to have analgesic effects via µ-opioid receptor activation and neuroinflammatory effects through Toll-like receptor 4 activation. Here we demonstrate that persistent memory deficits were mediated independently of the µ-opioid receptor, suggesting that they were evoked through a neuroinflammatory mechanism and unrelated to pain modulation. In support of this, aged, laparotomized, and morphine-treated rats exhibited increased gene expression of various proinflammatory markers (IL-1ß, IL-6, TNFα, NLRP3, HMGB1, TLR2, and TLR4) in the hippocampus at the 2-week time point. Furthermore, central blockade of IL-1ß signaling with the specific IL-1 receptor antagonist (IL-1RA), at the time of surgery, completely prevented the memory impairment. Finally, synaptophysin and PSD95 gene expression were significantly dysregulated in the hippocampus of aged, laparotomized, morphine-treated rats, suggesting that impaired synaptic structure and/or function may play a key role in this persistent deficit. This instance of long-term memory impairment following surgery closely mirrors the timeline of persistent POCD in humans and may be useful for future treatment discoveries.

The inhibitory effects of class I histone deacetylases on hippocampal neuroinflammatory regulation in aging mice with postoperative cognitive dysfunction.

OBJECTIVE: Neuroinflammation in the hippocampus has been determined to contribute to postoperative cognitive dysfunction (POCD) occurrence in elderly individuals. Histone deacetylases (HDACs) have been identified as important regulators of inflammation. However, the roles of different types of HDACs in POCD have never been fully explored. MATERIALS AND METHODS: POCD mouse models were established using isoflurane and validated by the Morris water maze test. The mice were pretreated with UF010 [a Class I HDAC inhibitor (HDACi)], MC1568 (a Class II HDACi) and SAHA (a Class I and II HDACi) before POCD establishment. HDAC protein levels and the activity of the NF-κB/p65, JAK/STAT and TLR/MyD88 signaling pathways in the hippocampus were investigated by Western blot (WB). The enrichment of HDACs on the promoters of genes was detected using ChIP-qPCR. RESULTS: Class I HDACs, including HDAC2 and HDAC8, and Class II HDACs, including HDAC4, HDAC7 and HDAC10, were all upregulated in the POCD group compared to the control group. Furthermore, compared to the MC1568 pretreatment group and the control group, the groups pretreated with UF010 and SAHA exhibited amelioration of the effects of anesthesia/surgery induced POCD and compromised inflammatory reactions in the hippocampus. Likewise, the NF-κB/p65, JAK/STAT and TLR/MyD88 signaling pathways were inactivated upon pretreatment with UF010 and SAHA compared to MC1568. Finally, the transcription of the genes negatively regulating these three pathways declined, and the enrichment of HDAC1, HDAC2 and HDAC8 was significantly elevated in the context of POCD. CONCLUSIONS: Class I HDACs, especially HDAC1, HDAC2 and HDAC8, play crucial roles in enhancing neuroinflammation in the hippocampus and causing POCD. Class I HDACs are potential therapeutic targets for POCD prevention and treatment via neuroinflammation inhibition.

Dexmedetomidine ameliorates postoperative cognitive dysfunction by inhibiting Toll-like receptor 4 signaling in aged mice.

Our study aimed to explore the molecular mechanisms involved in the improvement of postoperative cognitive dysfunction (POCD) by dexmedetomidine (DEX). BV2 microglia cells were cultured under normal condition, DEX exposure (0.1 µg/mL), and lipopolysacchride (LPS) treatment (0.1 µg/mL) or with pretreatment of DEX before LPS incubation. For BV2 microglia cells, LPS induced markedly increased release of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-alpha [TNF-α]) and expressions of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB), while DEX pretreatment inhibited the LPS-induced production of pro-inflammatory cytokines and expressions of TLR4 and NF-κB. The spatial memory function was impaired in the aged mice following partial hepatectomy since the percentage of time spent in the target quadrant and the number of crossings over the former platform location were reduced. Pretreatment of DEX may attenuate neuroinflammation and improve POCD in aged mice through inhibiting the TLR4-NF-κB signaling pathway in the hippocampus.