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1.
Curr Med Sci ; 44(2): 291-297, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38517674

ABSTRACT

Postoperative cognitive dysfunction (POCD) remains a major issue that worsens the prognosis of elderly surgery patients. This article reviews the current research on the effect of different anesthesia methods and commonly utilized anesthetics on the incidence of POCD in elderly patients, aiming to provide an understanding of the underlying mechanisms contributing to this condition and facilitate the development of more reasonable anesthesia protocols, ultimately reducing the incidence of POCD in elderly surgery patients.


Subject(s)
Anesthesia , Cognitive Dysfunction , Postoperative Cognitive Complications , Humans , Aged , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/epidemiology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/epidemiology , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Anesthesia/adverse effects , Anesthetics, Intravenous
2.
Aging (Albany NY) ; 16(4): 3763-3772, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38364258

ABSTRACT

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients. Liraglutide (LRG) has high homology (97%) with natural glucagon like peptide-1, and it has been proved to be effective in some nervous system diseases. Whether LRG could regulate POCD has not been reported. METHODS: Sevoflurane (Sev) was used to simulate postoperative cognitive dysfunction (POCD) model. Morris water maze test was performed to evaluate the memory ability and neurological function of rats. Escape latency, swim distance, crossing platform times, average velocity, and targeting quadrant time were analyzed. The cell apoptosis, mRNA and protein expression were measured through flow cytometry, PCR, and western blotting, respectively. RESULTS: LRG significantly improved the memory ability and neurological function of Sev-treated rats, but 3-MA reversed the effects of LRG. LRG remarkably inhibited apoptosis but up-regulated autophagy related proteins both in vivo and in vitro levels. However, knocking down AMPK could markedly reverse the influence of LRG on apoptosis, autophagy, and cell apoptosis. CONCLUSIONS: LRG induced autophagy activation can maintain cell homeostasis and promote cell survival by blocking the apoptotic pathway. LRG could improve Sev-induced POCD via activating autophagy, inhibiting apoptosis, and regulating AMPK/mTOR signaling pathway. This study provides a novel therapeutic strategy for the prevention and treatment of POCD.


Subject(s)
Cognitive Dysfunction , Postoperative Cognitive Complications , Humans , Rats , Animals , Aged , Liraglutide/pharmacology , Liraglutide/therapeutic use , Sevoflurane/adverse effects , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/prevention & control , AMP-Activated Protein Kinases/metabolism , Apoptosis , Autophagy , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy
3.
Anesth Analg ; 138(3): 589-597, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38100389

ABSTRACT

BACKGROUND: The goal of this study was to investigate the efficacy of neostigmine on postoperative cognitive dysfunction (POCD) and determine its effect on systematic markers of oxidative stress in older patients. METHODS: This double-blind placebo-controlled trial enrolled 118 elderly patients (≥65 years) undergoing noncardiac surgeries who were allocated to a neostigmine treatment group (0.04 mg/kg) or a placebo control group (normal saline) postoperatively. POCD was diagnosed if the Z -scores for the mini-mental state examination and the Montreal Cognitive Assessment were both ≤-1.96. Postoperative serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were also compared. Multivariable regression analysis with dose adjustment of atropine was used to demonstrate the influence of neostigmine on the incidence of POCD. RESULTS: Patients receiving neostigmine had a significantly reduced incidence of POCD compared to patients who were treated with placebo on the first day after surgery (-22%, 95% confidence interval [CI], -37 to -7), but not on the third (8%, 95% CI, -4 to 20) or seventh day after surgery (3%, 95% CI, -7 to 13). Postoperative plasma MDA levels were significantly lower ( P = .016), but SOD and BDNF levels were increased ( P = .036 and .013, respectively) in the neostigmine group compared to the control group on the first day after surgery. CONCLUSIONS: Neostigmine reduced POCD on the first day after noncardiac surgery in older patients. Neostigmine treatment inhibited oxidative stress and increased serum BDNF levels. There was no significant influence of neostigmine on POCD on the third or seventh day after surgery. The clinical influence of neostigmine on POCD should be further investigated.


Subject(s)
Cognitive Dysfunction , Postoperative Cognitive Complications , Aged , Humans , Brain-Derived Neurotrophic Factor , Cognitive Dysfunction/complications , Neostigmine/adverse effects , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/diagnosis , Postoperative Cognitive Complications/epidemiology , Postoperative Complications/chemically induced , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Superoxide Dismutase , Double-Blind Method
4.
PeerJ ; 11: e15466, 2023.
Article in English | MEDLINE | ID: mdl-37361037

ABSTRACT

Background: Postoperative cognitive dysfunction (POCD) is a clinically frequent postoperative complication in the elderly, which is mainly manifested by the occurrence of cognitive dysfunction after anesthetized surgery in patients. To explore the involvement of C/EBPα in microglial polarization in sevoflurane anesthesia induced cognitive impairment in aged rats. Methods: Sprague-Dawley (SD) rats were anesthetized by inhalation of 3% sevoflurane for 6 h to establish the POCD model. The histopathological structure of hippocampus was observed by hematoxylin and eosin (HE) staining. Associative learning and memory function and spatial learning and memory function were assessed by conditioned fear test and water maze test. The concentrations of inflammatory factors in the hippocampus were measured by ELISA. The levels of microglial activation marker (Iba1) and microglial M1 (CD86) and M2 (CD206) polarization markers were determined by immunofluorescence staining and RT-qPCR, respectively. The transcriptional regulation of HDAC1 by C/EBPα was confirmed by dual luciferase reporter assay and ChIP assay. Results: Sevoflurane-induced pathomorphological damage in the hippocampal tissue of aged rats, accompanied by elevated expression of C/EBPα. Silencing of C/EBPα alleviated hippocampal histopathological injury, inhibited M1 microglial activation and the expression of M1 marker CD86, enhanced the expression of M2 marker CD206. C/EBPα transcriptionally activated HDAC1. Knockdown of C/EBPα downregulated the expression of HDAC1 and STAT3 phosphorylated proteins, which inhibited the pro-inflammatory factors (IL-6 and TNF-α) and accelerated anti-inflammatory factors (IL-10 and TGF-ß) secretion. In addition, silencing of C/EBPα caused rats to have a delayed freezing time in contextual conditioned fear, a shorter escape latency, and an increased number of platform crossings. Conclusion: Inhibition of C/EBPα promotes the M2 polarization of microglia and reduces the production of pro-inflammatory cytokines to alleviate the cognitive dysfunction of sevoflurane-induced elderly rats by HDAC1/STAT3 pathway.


Subject(s)
CCAAT-Enhancer-Binding Proteins , Cognitive Dysfunction , Postoperative Cognitive Complications , Sevoflurane , Animals , Rats , Cognitive Dysfunction/chemically induced , Microglia , Postoperative Cognitive Complications/chemically induced , Rats, Sprague-Dawley , Sevoflurane/adverse effects , CCAAT-Enhancer-Binding Proteins/genetics
5.
J Biochem Mol Toxicol ; 37(6): e23340, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37041698

ABSTRACT

Postoperative cognitive dysfunction (POCD) is regularly observed in patients postsurgery due to the usage of anesthetics, including Sevoflurane. Research has confirmed the participation of oxidative stress (OS) and inflammation in the pathogenesis of POCD. Recently, the potential therapeutic function of miR-190a-3p against cognitive dysfunction has been reported. However, its role and mechanism in POCD are unclear. Our study will focus on the protective property and mechanism of miR-190a-3p on POCD to seek potential biomarkers and treatment targets for POCD. The animal model of POCD was constructed by the injection of Sevoflurane, followed by the administration of mimic negative control and miR-190a-3p. MiR-190a-3p was found to be downregulated in POCD rats. Declined time to explore the platform, swimming distance, and times that rats crossed the platform were observed in POCD rats, accompanied by increased secretion of proinflammatory cytokines, elevated malondialdehyde levels, repressed superoxide dismutase activity, and decreased levels of reduced glutathione, all of which were dramatically reversed by miR-190a-3p. Furthermore, the downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activation of toll-like receptor 4/nuclear factor-κB signaling were observed in POCD rats, which were greatly rescued by miR-190a-3p. Lastly, the Nrf2 luciferase activity and Nrf2 levels in HT22 cells were extremely improved by miR-190a-3p. Collectively, miR-190a-3p alleviated Sevoflurane-induced POCD in rats by repressing OS and inflammation.


Subject(s)
Cognitive Dysfunction , MicroRNAs , Postoperative Cognitive Complications , Rats , Animals , Postoperative Cognitive Complications/chemically induced , Sevoflurane/adverse effects , MicroRNAs/genetics , NF-E2-Related Factor 2/genetics , Cognitive Dysfunction/chemically induced , Inflammation/chemically induced , Inflammation/pathology
6.
Neurochem Res ; 48(6): 1848-1863, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36729311

ABSTRACT

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30 min per day) starting 24 h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.


Subject(s)
Basal Forebrain , Cognitive Dysfunction , Postoperative Cognitive Complications , Vagus Nerve Stimulation , Rats , Animals , Sevoflurane/toxicity , Rats, Sprague-Dawley , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Hippocampus/metabolism , Cholinergic Agents/metabolism , Cholinergic Agents/pharmacology , Cholinergic Neurons , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/prevention & control , Postoperative Cognitive Complications/metabolism
7.
Tissue Cell ; 81: 102012, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36608639

ABSTRACT

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.


Subject(s)
Cognitive Dysfunction , Postoperative Cognitive Complications , Animals , Rats , Brain-Derived Neurotrophic Factor/pharmacology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Hippocampus/pathology , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/genetics , Postoperative Cognitive Complications/metabolism , Sevoflurane/adverse effects , Signal Transduction , Transcription Factors/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Fibroblast Growth Factors/metabolism
8.
Neurotox Res ; 40(6): 1902-1912, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36308704

ABSTRACT

The objective of this study was to discuss the possible mechanism and effect of miR-182-5p delivered by plasma exosomes on sevoflurane-induced neuroinflammation and cognitive disorder in aged rats with postoperative cognitive dysfunction (POCD). Firstly, aged POCD rat models were constructed by sevoflurane anesthesia and superior mesenteric artery occlusion. Subsequently, exosomes and miR-182-5p were inhibited by injection of GW4869 and miR-182-5p-sponge, respectively. Then, exosomes were extracted from the plasma of rats in each group, followed by the determination of the morphology and diameters of exosomes as well as the expression of exosome markers CD63 and CD81 by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Besides, the Morris water maze (MWM) and fear conditioning test were used to evaluate the learning and memory ability of rats; Western blot to detect the expression levels of neurotrophic factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) as well as NF-κB pathway-related proteins (p65 and p-p65) in rat hippocampal tissues or PC-12 cells; qRT-PCR to assess the expression levels of miR-182-5p and BDNF in rat plasma, plasma exosomes, hippocampal tissues, and PC-12 cells; ELISA to evaluate the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß in rat hippocampal tissues; and dual-luciferase reporter assay to verify the targeting relationship between miR-182-5p and BDNF. After examination, the results were obtained as follows. miR-182-5p expression was up-regulated in POCD rats and could be delivered by plasma exosomes. Inhibition of plasma exosomes or miR-182-5p could significantly ameliorate learning and memory disorders; decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß; increase the expression of BDNF and NGF; and inhibit the activity of NF-κB signaling pathway in POCD rat hippocampus. In addition, miR-182-5p could also target and inhibit BDNF. All in all, miR-182-5p delivered by plasma exosomes promotes sevoflurane-induced neuroinflammation and cognitive dysfunction in aged POCD rats by targeting BDNF and activating the NF-κB pathway.


Subject(s)
Cognitive Dysfunction , Exosomes , MicroRNAs , Postoperative Cognitive Complications , Rats , Animals , NF-kappa B/metabolism , Sevoflurane/toxicity , Postoperative Cognitive Complications/chemically induced , Brain-Derived Neurotrophic Factor , Neuroinflammatory Diseases , Exosomes/metabolism , Nerve Growth Factor , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6 , MicroRNAs/metabolism
9.
Acta Biochim Biophys Sin (Shanghai) ; 54(7): 875-881, 2022 Jul 25.
Article in English | MEDLINE | ID: mdl-35713318

ABSTRACT

Postoperative cognitive dysfunction (POCD) is a common brain function-related complication after surgery. In addition to old age being an independent risk factor, anesthetics are also important predisposing factors. Among them, propofol is the most commonly used intravenous anesthetic in clinical practice. It has a rapid onset, short half-life, and high recovery quality. Many studies report that propofol can attenuate surgery-induced cognitive impairment, however, some other studies reveal that propofol also induces cognitive dysfunction. Therefore, this review summarizes the effects of propofol on the cognition, and discusses possible related mechanisms, which aims to provide some evidence for the follow-up studies.


Subject(s)
Anesthetics, Inhalation , Cognitive Dysfunction , Postoperative Cognitive Complications , Propofol , Anesthetics, Inhalation/adverse effects , Anesthetics, Intravenous/adverse effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/prevention & control , Humans , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/prevention & control , Postoperative Complications/chemically induced , Postoperative Complications/prevention & control , Propofol/adverse effects
10.
Hum Exp Toxicol ; 41: 9603271211061497, 2022.
Article in English | MEDLINE | ID: mdl-35187972

ABSTRACT

BACKGROUND: As a common postoperative complication to elderly patients, postoperative cognitive dysfunction (POCD) is a central nervous system complication, often taking place after anesthesia and surgery. (Su(var)3-9, enhancer-of-zeste, and trithorax) domain-containing protein 7 (SETD7) plays important roles in metabolic-related diseases, viral infections, tumor formation, and some inflammatory reactions. However, the role and mechanism of SETD7 in POCD have not been previously studied. METHODS: RT-PCR and Western blot were performed to evaluate the efficiency of knockdown of SETD7. The pathological changes of hippocampal neurons in isoflurane-anesthetized mice were detected by HE staining, and the Morris water maze experiment was performed to evaluate the learning and memory abilities of mice. The effect of SETD7 on the hippocampus in isoflurane-induced aged mice was examined by Western blot and TUNEL assay. Then ELISA assay was applied to determine the expression of some inflammatory cytokines, followed by the detection of expression of NOD-like receptor protein 3 (NLRP3) inflammasome through Western blot. RESULTS: The data of this research revealed that SETD7 knockdown improved cognitive impairment in isoflurane-anesthetized mice, ameliorated cell pyroptosis, inhibited the release of inflammatory cytokines, and suppressed the activation of NLRP3 inflammasome in the hippocampus in isoflurane-induced aged mice. CONCLUSION: Collectively, these results provided evidence that the inhibition of SETD7 could alleviate neuroinflammation, pyroptosis, and cognitive impairment by suppressing the activation of the NLRP3 inflammasome in isoflurane-induced aged mice.


Subject(s)
Anesthetics, Inhalation/adverse effects , Gene Knockdown Techniques , Inflammasomes/metabolism , Methyltransferases/metabolism , NLR Proteins/metabolism , PR-SET Domains/genetics , Postoperative Cognitive Complications/chemically induced , Aging/drug effects , Animals , Disease Models, Animal , Inflammasomes/genetics , Isoflurane/adverse effects , Male , Methyltransferases/genetics , Mice , NLR Proteins/genetics
11.
Medicine (Baltimore) ; 100(43): e27668, 2021 Oct 29.
Article in English | MEDLINE | ID: mdl-34713863

ABSTRACT

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a very common event in elderly noncardiac surgical patients. The effects of inhalational anaesthetics and propofol on the incidence of POCD and postoperative cognitive status at different time points after surgery are currently unclear. METHODS: We searched the Embase, Medline, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs), in which inhalation anaesthesia and propofol anaesthesia were compared. The incidence of POCD or postoperative cognitive status was assessed in elderly patients undergoing noncardiac surgery. RESULTS: Fifteen RCTs with 1854 patients were included in this meta-analysis. The incidence of POCD on postoperative Days 2-6 after propofol anaesthesia was markedly lower than that after inhalation anaesthesia (risk ratio (RR): 0.37, 95% confidence interval (CI): 0.15-0.88, P = .025), and Mini-Mental State Examination (MMSE) scores after propofol anaesthesia were substantially higher than those after inhalation anaesthesia (standard mean difference (SMD): 0.59, 95% CI: 0.07-1.11, P = .026). The levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were much lower after propofol anaesthesia than after inhalation anaesthesia (SMD: -2.027, 95% CI: -3.748- -0.307, P = .021; SMD: -0.68, 95% CI: -0.93- -0.43, P < .001). CONCLUSIONS: The moderate evidence from this meta-analysis shows that, in elderly noncardiac surgical patients, propofol anaesthesia is superior to inhalation anaesthesia for attenuating of early POCD incidence, and low-level evidence shows that cognitive status is higher and systemic inflammation is less severe after propofol anaesthesia in the early days after surgery. LIMITATIONS: The sample size was not sufficiently large for systemic inflammation, and the tools to identify POCD were not uniform in the included studies.


Subject(s)
Anesthesia, Inhalation/adverse effects , Anesthetics, Inhalation/adverse effects , Anesthetics, Intravenous/adverse effects , Postoperative Cognitive Complications/chemically induced , Propofol/adverse effects , Anesthetics, Inhalation/therapeutic use , Anesthetics, Intravenous/therapeutic use , Humans , Mental Status and Dementia Tests , Propofol/therapeutic use , Randomized Controlled Trials as Topic , Surgical Procedures, Operative/adverse effects , Surgical Procedures, Operative/methods
12.
Aging (Albany NY) ; 13(19): 23108-23118, 2021 10 05.
Article in English | MEDLINE | ID: mdl-34611079

ABSTRACT

Elderly patients are prone to cognitive impairment and memory loss after surgical operations. This perioperative cerebral damage, named postoperative cognitive dysfunction (POCD), is profoundly affected by anesthesia. N6-methyladenosine (m6A) RNA methylation is a widely-studied epigenetic modification to regulate gene expression; however, is has never been studied in POCD. In the present study, elderly POCD mouse models were constructed using sevoflurane, and we observed a compromised global m6A RNA methylation in the mice's hippocampuses compared with the control. Our RIP-Seq data suggested that 1244 genes (SOX2, SYN1, and BDNF) showed m6A RNA methylation in their 5'UTRs, which was significantly lower than that in the control; while only 56 genes (BACE1 and IL17A) showed m6A RNA methylation in their 5'UTRs, which was significantly higher than that in the control. Unexpectedly, m6A RNA methylation with significant differences in exons, introns, or 3'UTRs was observed in only few genes. Although we failed to find any differences in the expression of m6A-associated proteins, such as m6A "writers", "erasers", and "readers", between the sevoflurane treatment and control groups, RIP-qPCR assays indicated that the binding affinity of METTL3 on mRNA 5'UTRs was particularly weakened in target genes by sevoflurane. Finally, we found that phosphorylation of METTL3 could be reduced by sevoflurane because of the inactivation of the MAPK/ERK pathway. Overall, our study determined that the inactivation of METTL3 in the mouse hippocampus, induced by sevoflurane-mediated MAPK/ERK suppression in vivo, resulted in a perturbation in m6A RNA methylation signals in the pathogenesis of POCD.


Subject(s)
Adenosine/analogs & derivatives , DNA Methylation/genetics , Methyltransferases/genetics , Postoperative Cognitive Complications , Sevoflurane/adverse effects , Adenosine/genetics , Animals , Disease Models, Animal , Female , Hippocampus/drug effects , Hippocampus/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Inbred C57BL , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/metabolism , Transcription, Genetic/genetics
13.
J Neurophysiol ; 125(6): 2117-2124, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33949883

ABSTRACT

Sevoflurane anesthesia is correlated with the generation of postoperative cognitive dysfunction. Insulin-like growth factor 1 (IGF-1) has important function in the nervous system development. Intravenously injected IGF-1 is reported to successfully pass the blood-brain barrier and perform neuroprotection effect in the brain. Memory and learning abilities were analyzed through Morris water maze task. Relative levels of protein were examined through Western blot and enzyme-linked immunosorbent assay (ELISA). Relative mRNA levels were shown through quantitative real-time polymerase chain reaction (qRT-PCR). IGF-1 expression in the plasma and hippocampus was downregulated in sevoflurane anesthesia-induced rats and rescued by intravenous IGF-1 injection. In aged rats, intravenous injection of IGF-1 alleviated sevoflurane-caused cognitive injuries and elevated TNF-α, IL-1ß, and IL-6 levels in the plasma and hippocampus and rescued sevoflurane-depressed Akt phosphorylation. In conclusion, the administration of IGF-1 through intravenous injection alleviates sevoflurane anesthesia-mediated neuroinflammation and cognitive impairment in rats. The effects of IGF-1 in this process may depend on its function in regulating the PI3K/Akt signaling pathway.NEW & NOTEWORTHY IGF-1 expression was downregulated by sevoflurane anesthesia in rats and could be rescued by intravenous IGF-1 injection, which alleviated sevoflurane-caused cognitive injuries and enhanced inflammatory responses in aged rats. Intravenous injection of IGF-1 rescued sevoflurane-depressed Akt phosphorylation in aged rats.


Subject(s)
Aging , Anesthetics, Inhalation/adverse effects , Hippocampus/drug effects , Insulin-Like Growth Factor I/pharmacology , Neuroinflammatory Diseases/drug therapy , Neuroprotective Agents/pharmacology , Postoperative Cognitive Complications/drug therapy , Sevoflurane/adverse effects , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Disease Models, Animal , Down-Regulation , Hippocampus/metabolism , Injections, Intravenous , Insulin-Like Growth Factor I/administration & dosage , Insulin-Like Growth Factor I/drug effects , Insulin-Like Growth Factor I/metabolism , Maze Learning/drug effects , Maze Learning/physiology , Neuroinflammatory Diseases/chemically induced , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/physiopathology , Neuroprotective Agents/administration & dosage , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/metabolism , Postoperative Cognitive Complications/physiopathology , Rats , Rats, Sprague-Dawley
14.
PLoS One ; 16(3): e0247678, 2021.
Article in English | MEDLINE | ID: mdl-33770816

ABSTRACT

Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.


Subject(s)
Anesthesia, General/adverse effects , Anesthetics, Inhalation/adverse effects , Brain/pathology , Postoperative Cognitive Complications/pathology , Sevoflurane/adverse effects , White Matter/pathology , Adult , Aged , Aged, 80 and over , Brain/diagnostic imaging , Brain/drug effects , Brain Mapping , Case-Control Studies , Diffusion Tensor Imaging , Female , Gray Matter/diagnostic imaging , Gray Matter/drug effects , Gray Matter/pathology , Humans , Male , Middle Aged , Neuroglia/drug effects , Neuroglia/pathology , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/diagnostic imaging , White Matter/diagnostic imaging , White Matter/drug effects
15.
J Neuroinflammation ; 18(1): 41, 2021 Feb 04.
Article in English | MEDLINE | ID: mdl-33541361

ABSTRACT

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a very common complication that might increase the morbidity and mortality of elderly patients after surgery. However, the mechanism of POCD remains largely unknown. The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is located in the mitochondria and regulates mitochondrial function. SIRT3 is the only sirtuin that specifically plays a role in extending lifespan in humans and is associated with neurodegenerative diseases. Therefore, the aim of this study was to evaluate the effect of SIRT3 on anesthesia/surgery-induced cognitive impairment in aged mice. METHODS: SIRT3 expression levels were decreased after surgery. For the interventional study, an adeno-associated virus (AAV)-SIRT3 vector or an empty vector was microinjected into hippocampal CA1 region before anesthesia/surgery. Western blotting, immunofluorescence staining, and enzyme-linked immune-sorbent assay (ELISA) were used to measure the oxidative stress response and downstream microglial activation and proinflammatory cytokines, and Golgi staining and long-term potentiation (LTP) recording were applied to evaluate synaptic plasticity. RESULTS: Overexpression of SIRT3 in the CA1 region attenuated anesthesia/surgery-induced learning and memory dysfunction as well as synaptic plasticity dysfunction and the oxidative stress response (superoxide dismutase [SOD] and malondialdehyde [MDA]) in aged mice with POCD. In addition, microglia activation (ionized calcium binding adapter molecule 1 [Iba1]) and neuroinflammatory cytokine levels (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1ß and IL-6) were regulated after anesthesia/surgery in a SIRT3-dependent manner. CONCLUSION: The results of the current study demonstrate that SIRT3 has a critical effect in the mechanism of POCD in aged mice by suppressing hippocampal neuroinflammation and reveal that SIRT3 may be a promising therapeutic and diagnostic target for POCD.


Subject(s)
Aging/metabolism , Anesthetics, Inhalation/toxicity , Hippocampus/metabolism , Inflammation Mediators/metabolism , Postoperative Cognitive Complications/metabolism , Sirtuin 3/biosynthesis , Aging/drug effects , Aging/pathology , Animals , Hippocampus/drug effects , Hippocampus/pathology , Inflammation Mediators/antagonists & inhibitors , Isoflurane/toxicity , Male , Mice , Mice, Inbred C57BL , Neuroprotection/drug effects , Neuroprotection/physiology , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/etiology , Postoperative Cognitive Complications/prevention & control , Tibial Fractures/surgery
16.
Medicine (Baltimore) ; 100(4): e23930, 2021 Jan 29.
Article in English | MEDLINE | ID: mdl-33530193

ABSTRACT

BACKGROUND: To investigate whether closed-loop systems under bispectral index anesthesia depth monitoring can reduce the intraoperative propofol dosage. METHODS: All randomized controlled trials (RCTs) on reducing propofol dosage under closed-loop systems were collected, and the literature was screened out, the abstracts and full texts were carefully read, and the references were tracked, data extraction and quality evaluation were conducted on the included research, and the RevMan5.3 software was used for meta-analysis. The main results were propofol and the incidence of adverse reactions such as hypertensive hypotension and postoperative cognitive dysfunction. A total of 879 cases were included in 8 articles, including 450 occurrences in the closed-loop system group and 429 cases in the open-loop system group. RESULTS: Compared with manual control, closed-loop systems under bispectral index anesthesia depth monitoring reduced the dose of propofol (MD: -0.62, 95% CI: -1.08--0.16, P = .008), with heterogeneity (I2 = 80%). Closed-loop systems significantly reduced the incidence of abnormal blood pressure (MD: -0.02, 95%CI: -0.05-0.01, P = .15, I2 = 74%) and postoperative cognitive dysfunction (MD: -0.08, 95% CI: -0.14 -0.01, P = .02, I2 = 94%). CONCLUSION: Bispectral index monitoring of propofol closed-loop target-controlled infusion system can reduce the amount of propofol, reduce the incidence of adverse reactions such as hypertensive or hypotension and postoperative cognitive dysfunction.


Subject(s)
Anesthetics, Intravenous/therapeutic use , Consciousness Monitors , Propofol/therapeutic use , Anesthesia, Intravenous/methods , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/adverse effects , Dose-Response Relationship, Drug , Humans , Postoperative Cognitive Complications/chemically induced , Propofol/administration & dosage , Propofol/adverse effects , Randomized Controlled Trials as Topic
17.
Hum Cell ; 34(3): 808-818, 2021 May.
Article in English | MEDLINE | ID: mdl-33616869

ABSTRACT

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.


Subject(s)
Anesthetics, Inhalation/adverse effects , Lim Kinases/metabolism , MicroRNAs/metabolism , Neuroprotective Agents , Nuclear Proteins/pharmacology , Nuclear Proteins/physiology , Postoperative Cognitive Complications/drug therapy , Postoperative Cognitive Complications/genetics , Sevoflurane/adverse effects , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Survival/drug effects , Cell Survival/genetics , Gene Expression/drug effects , Gene Expression/genetics , Hippocampus/cytology , L-Lactate Dehydrogenase/metabolism , Lim Kinases/genetics , Mice , MicroRNAs/genetics , Neurons/metabolism , Neurons/physiology , Nuclear Proteins/administration & dosage , Postoperative Cognitive Complications/chemically induced
18.
Neurobiol Aging ; 98: 214-224, 2021 02.
Article in English | MEDLINE | ID: mdl-33341652

ABSTRACT

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.


Subject(s)
Aging , Morphine/adverse effects , Postoperative Cognitive Complications/chemically induced , Alzheimer Disease/etiology , Animals , Cytokines/genetics , Cytokines/metabolism , Gene Expression , Hippocampus/metabolism , Inflammation Mediators/metabolism , Laparotomy , Memory Disorders/chemically induced , Memory Disorders/genetics , Memory Disorders/psychology , Memory, Long-Term , Memory, Short-Term , Morphine/metabolism , Postoperative Cognitive Complications/genetics , Postoperative Cognitive Complications/psychology , Rats , Receptors, Opioid, mu/metabolism , Toll-Like Receptor 4/metabolism
19.
Anesth Analg ; 133(4): 837-847, 2021 10 01.
Article in English | MEDLINE | ID: mdl-33181558

ABSTRACT

BACKGROUND: The aim of the study was to investigate whether closed-loop compared to manual bispectral index (BIS)-guided target-controlled infusion of propofol and remifentanil could decrease the incidence of postoperative neurocognitive disorders after elective major noncardiac surgery. METHODS: Patients aged >50 admitted for elective major noncardiac surgery were included in a single-blind randomized (ratio 2:1) trial. The anesthetic protocol was allocated by randomization into either closed-loop or manual BIS-guided propofol and remifentanil titration. The BIS target range was 40-60. All patients had cognitive assessment the day before surgery and within 72 hours after surgery using a battery of neuropsychological tests. The primary outcome was the rate of postoperative neurocognitive disorders. Postoperative neurocognitive disorders were defined as a decrease >20% from baseline on at least 3 scores. Intergroup comparison of the primary outcome was performed using the χ2 test. RESULTS: A total of 143 and 61 patients were included in the closed-loop and manual groups, respectively (age: 66 [8] vs 66 [9] years). The primary outcome was observed in 18 (13%) and 10 (16%) patients of the closed-loop and manual groups, respectively (relative risk [95% confidence interval {CI}], 0.77 [0.38-1.57], P = .47). Intraoperative propofol consumption was lower (4.7 [1.4] vs 5.7 [1.4] mg·kg-1·h-1, mean difference [MD] [95% CI], -0.73 [-0.98 to -0.48], P < .0001) and the proportion of time within the BIS target range higher (84 [77-89] vs 74 [54-81]%, MD [95% CI], 0.94 [0.67-1.21], P < .0001) in the closed-loop group. CONCLUSIONS: Closed-loop compared to manual BIS-guided total intravenous anesthesia provided a significant reduction in episodes of an excessive depth of anesthesia while decreasing intraoperative propofol requirement but no evidence for a reduction of the incidence of postoperative neurocognitive disorders after elective major noncardiac surgery was observed.


Subject(s)
Anesthesia, Closed-Circuit , Anesthesia, Intravenous , Anesthetics, Intravenous/administration & dosage , Electroencephalography , Intraoperative Neurophysiological Monitoring , Postoperative Cognitive Complications/prevention & control , Propofol/administration & dosage , Remifentanil/administration & dosage , Aged , Anesthesia, Closed-Circuit/adverse effects , Anesthesia, Intravenous/adverse effects , Anesthetics, Intravenous/adverse effects , Elective Surgical Procedures , Female , France , Humans , Infusions, Intravenous , Male , Middle Aged , Postoperative Cognitive Complications/chemically induced , Postoperative Cognitive Complications/diagnosis , Postoperative Cognitive Complications/physiopathology , Propofol/adverse effects , Remifentanil/adverse effects , Risk Factors , Single-Blind Method , Time Factors , Treatment Outcome
20.
Medicine (Baltimore) ; 99(36): e21859, 2020 Sep 04.
Article in English | MEDLINE | ID: mdl-32899015

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate the effects of adding ketamine to propofol on cognitive functions in patients undergoing sedation for colonoscopy. METHODS: In this randomized, double-blinded, and controlled study, 200 patients were randomly allocated to ketamine/propofol admixture group (Group KP, n = 100), and propofol group (Group P, n = 100). Patients in Group KP received 0.25 mg/kg of ketamine and 0.5 mg/kg of propofol. Patients in Group P received 0.5 mg/kg propofol. Cognitive functions were measured using CogState battery before and after the colonoscopy procedure. Ninety five patients in Group KP and 92 patients in Group P had completed the CogStates tests and were included in the data analysis. RESULTS: Compared with before procedure baseline, the performance on detection and identification tasks were significantly impaired after the procedure in both Group KP (P = .004, P = .001) and Group P patients (P = .005, P < .001). However, one-card learning accuracy and One-back memory was only impaired in Group KP patients (P = .006, P = .040) after the endoscopy but left intact in Group P patients. Group KP patients showed more severe impairment in one-card learning accuracy compared with Group P patients (P = .044). Group KP patients have better 5 minutes MAP (P = .005) and were also less likely to suffer from complications such as respiratory depression (P = .023) and hypotension (P = .015). OAA/S scores, BIS, MAP, complications, recovery times, and endoscopist and patient satisfaction were similar between the 2 groups. CONCLUSION: Although adding ketamine to propofol for sedation in colonoscopy provided fewer complications such as respiratory depression and hypotension, it also causes more impairment in cognitive functions.


Subject(s)
Colonoscopy/methods , Deep Sedation/methods , Hypnotics and Sedatives/pharmacology , Ketamine/pharmacology , Postoperative Cognitive Complications/chemically induced , Propofol/pharmacology , Adult , Deep Sedation/adverse effects , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Hypnotics and Sedatives/administration & dosage , Ketamine/administration & dosage , Male , Middle Aged , Propofol/administration & dosage , Prospective Studies , Randomized Controlled Trials as Topic
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