RESUMO
Postoperative cognitive dysfunction (POCD) is a common complication in elderly surgical patients, significantly affecting their quality of life. Dexmedetomidine (Dex), an anesthetic, has shown promise in alleviating POCD, but its underlying mechanism remains unclear. This study aims to explore how Dex improves POCD in aged rats by targeting the PINK1-mediated mitochondrial autophagy pathway, reducing caspase-1/11-GSDMD-induced hippocampal neuronal pyroptosis. Transcriptome sequencing identified 300 differentially expressed genes enriched in the mitochondrial autophagy pathway in Dex-treated POCD rat hippocampal tissue, with Pink1 as a key candidate. In a POCD rat model, Dex treatment upregulated hippocampal PINK1 expression. In vitro experiments using H19-7 rat hippocampal neurons revealed that Dex enhanced mitochondrial autophagy and suppressed neuronal pyroptosis by upregulating PINK1. Further mechanistic validation demonstrated that Dex activated PINK1-mediated mitochondrial autophagy, inhibiting caspase-1/11-GSDMD-induced neuronal pyroptosis. In vivo experiments confirmed Dex's ability to reduce caspase-1/11-GSDMD-dependent hippocampal neuronal pyroptosis and improve postoperative cognitive function in aged rats. Dexmedetomidine improves postoperative cognitive dysfunction in elderly rats by enhancing mitochondrial autophagy via PINK1 upregulation, mitigating caspase-1/11-GSDMD-induced neuronal pyroptosis.
Assuntos
Dexmedetomidina , Hipocampo , Mitofagia , Neurônios , Complicações Cognitivas Pós-Operatórias , Proteínas Quinases , Piroptose , Ratos Sprague-Dawley , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Ratos , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/metabolismo , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Piroptose/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Envelhecimento/efeitos dos fármacosRESUMO
Neuroinflammation is a major driver of postoperative cognitive dysfunction (POCD). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling is a prominent alarming device for aberrant double-stranded DNA (dsDNA) that has emerged as a key mediator of neuroinflammation in cognitive-related diseases. However, the role of the cGAS-STING pathway in the pathogenesis of POCD remains unclear. A POCD model was developed in male C57BL/6J mice by laparotomy under isoflurane (Iso) anesthesia. The cGAS inhibitor RU.521 and caspase-3 agonist Raptinal were delivered by intraperitoneal administration. BV2 cells were exposed to Iso and lipopolysaccharide (LPS) in the absence or presence of RU.521, and then cocultured with HT22 cells in the absence or presence of Raptinal. Cognitive function was assessed using the Morris water maze test and novel object recognition test. Immunofluorescence assays were used to observe the colocalization of dsDNA and cGAS. The downstream proteins and pro-inflammatory cytokines were detected using the Western blot and enzyme-linked immunosorbent assay (ELISA). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to assess the degree of cell death in the hippocampus following anesthesia/surgery treatment. Isoflurane/laparotomy and Iso + LPS significantly augmented the levels of cGAS in the hippocampus and BV2 cells, accompanied by mislocalized dsDNA accumulation in the cytoplasm. RU.521 alleviated cognitive impairment, diminished the levels of 2'3'-cGAMP, cGAS, STING, phosphorylated NF-κB p65 and NF-κB-pertinent pro-inflammatory cytokines (TNFα and IL-6), and repressed pyroptosis-associated elements containing cleaved caspase-3, N-GSDME, IL-1ß and IL-18. These phenotypes could be rescued by Raptinal in vivo and in vitro. These findings suggest that pharmacological inhibition of cGAS mitigates neuroinflammatory burden of POCD by dampening caspase-3/GSDME-dependent pyroptosis, providing a potential therapeutic strategy for POCD.
Assuntos
Caspase 3 , Camundongos Endogâmicos C57BL , Nucleotidiltransferases , Complicações Cognitivas Pós-Operatórias , Piroptose , Animais , Masculino , Camundongos , Piroptose/efeitos dos fármacos , Piroptose/fisiologia , Complicações Cognitivas Pós-Operatórias/metabolismo , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Caspase 3/metabolismoRESUMO
BACKGROUND: Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism. METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist. RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31. CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.
Assuntos
DNA Mitocondrial , Mitofagia , Complicações Cognitivas Pós-Operatórias , Animais , Humanos , Lactente , Camundongos , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Mitocôndrias , Mitofagia/efeitos dos fármacos , Doenças Neuroinflamatórias , Nucleotidiltransferases/efeitos dos fármacos , Nucleotidiltransferases/metabolismo , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismoRESUMO
Postoperative cognitive dysfunction (POCD) is a significant concern for the elderly population worldwide. This study explored the effects of esketamine on aged mice with POCD and investigate its mechanism of action involving the TLR4/MyD88/MAPK pathway. We administrated esketamine, along with lipopolysaccharide or anisomycin, to the aged POCD mouse models. We assessed their cognitive function using the Morris water maze test. Additionally, we evaluated histopathological changes/neuronal apoptosis in the mouse hippocampal CA1 area through HE/TUNEL stainings. Furthermore, we measured IL-1ß/IL-6/TNF-α/TLR4/MyD88/MAPK (p-p38/p38) levels in mouse hippocampal tissues using ELISA/RT-qPCR/Western blotting. Lastly, we analyzed the interaction between TLR4 and MyD88 using a co-immunoprecipitation assay. Our findings showed that esketamine effectively mitigated POCD in aged mice. This was evident from the improved cognitive performance observed in the Morris water maze test, characterized by reduced escape latency/increased number of platform crossing/a higher percentage of time spent in the target quadrant. Furthermore, esketamine exhibited a protective effect against neuronal apoptosis and reduced the levels of inflammatory factors. These findings suggest that esketamine exerts an anti-inflammatory effect by downregulating TLR4/MyD88, thereby attenuating the inflammatory response associated with POCD. Additionally, esketamine suppressed the p38 MAPK pathway by inhibiting the TLR4/MyD88 signaling cascade. Esketamine demonstrated its efficacy in improving postoperative inflammation and cognitive impairment in aged mice by inhibiting the TLR4/MyD88 pathway. The activation of p38 MAPK signaling diminished the beneficial effects of esketamine in aged POCD mice. Collectively, the underlying mechanism of esketamine in mitigating POCD in aged mice involves the suppression of the TLR4/MyD88/p38 MAPK pathway.
Assuntos
Disfunção Cognitiva , Ketamina , Complicações Cognitivas Pós-Operatórias , Humanos , Idoso , Camundongos , Animais , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Disfunção Cognitiva/tratamento farmacológico , NF-kappa B/metabolismoRESUMO
BACKGROUND: Perioperative neurocognitive disorder (PND) remains a prevalent complication following anesthesia and surgery. Recent studies have revealed the therapeutic potential of gastrodin (GAS) in treating cognitive disturbances. This study delves deeper into the mechanisms through which GAS impacts PND. METHODS: Male C57BL/6 mice (18 months old) underwent laparotomies and were administered GAS orally daily for three weeks preceding surgery and one week post-surgery. Thirty minutes before GAS administration, an intraperitoneal injection of Compound C was given. In vitro, H2O2-incubated SH-SY-5Y cells, with or without Nrf2-siRNA transfection, were set up and subjected to GAS or Compound C treatments. Cell viability was assessed via MTT assays, and apoptosis levels were assessed through flow cytometry. Cognitive function was evaluated using the Morris water maze, novel object recognition, and Y-maze tests. Oxidative stress markers, including MDA, SOD, GSH, GSH-px, and intracellular ROS (determined through immunofluorescence), were quantified. The expression of the genes Caspase3, Bax, Bcl-2, GST, and NQO1 was gauged using real-time RT-PCR. Brain, cortex and hippocampal pathologies were examined with hematoxylin-eosin (HE) and NeuN/TUNEL costaining. Finally, Nrf2 and p-AMPK were analyzed using Western blotting (WB) and immunofluorescence assays. RESULTS: GAS improved cognitive dysfunction in PND mice and reduced oxidative stress, neuro-apoptosis, and ROS levels both in vivo and in vitro experiment. In vivo, Immunofluorescence and Western blot outcomes indicated that postoperative p-AMPK and Nrf2 levels in the hippocampus were mitigated but were augmented by GAS. In vitro studies revealed GAS's protective effect against H2O2-induced oxidative stress and apoptosis and its upregulation of p-AMPK and Nrf2 in SH-SY-5Y cells. Notably, this protective effect was negated when Nrf2 siRNA was introduced. ELISA and PCR results highlighted the role of GAS in enhancing GST and NQO1 activity in both the mice hippocampus and SH-SY-5Y cells. Compound C, an AMPK inhibitor, both in vitro and in vivo, reversed the beneficial effects of GAS on Nuc-Nrf2/Cyt-Nrf2 expression and counteracted the positive influence of GAS on cognitive functions in PND mice. CONCLUSION: GAS facilitates the nuclear translocation of Nrf2 via AMPK activation, offering a therapeutic avenue for alleviating postoperative cognitive impairments in mice, with a significant reduction in oxidative stress.
Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Camundongos , Masculino , Animais , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Peróxido de Hidrogênio/farmacologia , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Disfunção Cognitiva/tratamento farmacológico , RNA Interferente Pequeno/metabolismoRESUMO
Post-operative cognitive dysfunction (POCD) is a common complication after surgery due to the usage of anesthetics, such as Sevoflurane, which severely impacts the life quality of patients. Currently, the pathogenesis of Sevoflurane-induced POCD has not been fully elucidated but is reportedly involved with oxidative stress (OS) injury and aggravated inflammation. Phoenixin-20 (PNX-20) is a PNX peptide consisting of 20 amino acids with promising inhibitory effects on OS and inflammation. Herein, we proposed to explore the potential protective function of PNX-20 on Sevoflurane inhalation-induced POCD in rats. Sprague-Dawley (SD) rats were treated with 100 ng/g PNX-20 for 7 days with or without pre-inhalation with 2.2% Sevoflurane. Markedly increased escape latency and decreased time in the target quadrant in the Morris water maze (MWM) test, and aggravated pathological changes and apoptosis in the hippocampus tissue were observed in Sevoflurane-treated rats, which were markedly attenuated by PNX-20. Furthermore, the aggravated inflammation and OS in the hippocampus observed in Sevoflurane-treated rats were notably abolished by PNX-20. Moreover, the brain-derived neurotrophic factor (BDNF), protein kinase A (PKA), and phospho-cAMP response element binding protein/cAMP response element binding protein (p-CREB/CREB) levels were markedly decreased in Sevoflurane-treated rats, which were memorably increased by PNX-20. Our results indicated that PNX-20 ameliorated Sevoflurane inhalation-induced POCD in rats via the activation of PKA/CREB signaling, which might supply a new treatment approach for POCD.
Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Animais , Humanos , Ratos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/metabolismo , Ratos Sprague-Dawley , Sevoflurano/efeitos adversos , Sevoflurano/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/efeitos dos fármacos , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismoRESUMO
Postoperative neurocognitive dysfunction (PND) is a common postoperative complication. Autophagy is correlated with the pathogenesis of PND. This study investigated the potential role of autophagy in the neuroprotection of dexmedetomidine (Dex) pretreatment in PND. The PND rat model was established by abdominal surgery. The cognitive function of rats was evaluated by Y-maze 3 days after surgery. Nissl staining assessed postoperative hippocampal damage. Immunofluorescence detected the expression of microglial activation (Iba-1) and autophagy-related protein (LC3B) in hippocampal tissues. Western blot detected the autophagy-related protein expression (Beclin 1, LC3B, and p62), proinflammatory cytokines, and the protein activation of the autophagy-related LKB1/AMPK/ULK-1 signaling pathway. RT-PCR quantified the expression of IL-1ß, TNF-α, and IL6. In this study, we found that Dex pretreatment improved spatial memory function impairment and reduced abdominal surgery-induced hippocampal tissue damage. Dex pretreatment significantly increased the expression of Beclin 1 and LC3 II/I and decreased the expression of p62 in the hippocampus after surgery. Furthermore, Dex effectively inhibited microglial activation and proinflammatory cytokines by enhancing autophagy in the hippocampus. Pretreatment with 3-MA, an autophagy inhibitor, significantly weakened the inhibitory effect of Dex on postoperative neuroinflammation. We further demonstrated that Dex suppressed surgery-induced neuroinflammation by activating the LKB1/AMPK/ULK-1 signaling pathway. In conclusion, our study indicated that Dex inhibited hippocampal neuroinflammation and ameliorated PND by enhancing autophagy after surgery in rats, which was related to the LKB1/AMPK/ULK-1 signaling pathway. These findings provide a potential therapeutic prospect for PND.NEW & NOTEWORTHY Dex inhibits hippocampal neuroinflammation and attenuates early cognitive impairment by enhancing autophagy following surgery in rats. Dex may protect postoperative cognitive function by activating the LKB1/AMPK/ULK-1 signaling pathway.
Assuntos
Disfunção Cognitiva , Dexmedetomidina , Complicações Cognitivas Pós-Operatórias , Ratos , Animais , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Ratos Sprague-Dawley , Doenças Neuroinflamatórias , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Citocinas , Hipocampo/metabolismo , AutofagiaRESUMO
The transversus thoracis muscle plane (TTMP) block provides effective analgesia in cardiac surgery patients. The aim of this study was to assess whether bilateral TTMP blocks can reduce the incidence of postoperative cognitive dysfunction (POCD) in patients undergoing cardiac valve replacement. A group of 103 patients were randomly divided into the TTM group (n = 52) and the PLA (placebo) group (n = 51). The primary endpoint was the incidence of POCD at 1 week after surgery. Secondary outcome measures included a reduction of intraoperative mean arterial pressure (MAP) >20% from baseline, intraoperative and postoperative sufentanil consumption, length of stay in the ICU, incidence of postoperative nausea and vomiting (PONV), time to first faeces, postoperative pain at 24 h after surgery, time to extubation and the length of hospital stay. Interleukin (IL)-6, TNF-α, S-100ß, insulin, glucose and insulin resistance were measured at before induction of anaesthesia, 1, 3and 7 days after surgery. The MoCA scores were significantly lower and the incidence of POCD decreased significantly in TTM group compared with PLA group at 7 days after surgery. Perioperative sufentanil consumption, the incidence of PONV and intraoperative MAP reduction >20% from baseline, length of stay in the ICU, postoperative pain at 24 h after surgery, time to extubation and the length of hospital stay were significantly decreased in the TTM group. Postoperatively, IL-6, TNF-α, S-100ß, HOMA-IR, insulin, glucose levels increased and the TTM group had a lower degree than the PLA group at 1, 3 and 7 days after surgery. In summary, bilateral TTMP blocks could improve postoperative cognitive function in patients undergoing cardiac valve replacement.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Insulinas , Complicações Cognitivas Pós-Operatórias , Humanos , Sufentanil/uso terapêutico , Analgésicos Opioides/uso terapêutico , Náusea e Vômito Pós-Operatórios/complicações , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Fator de Necrose Tumoral alfa , Subunidade beta da Proteína Ligante de Cálcio S100 , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Glucose , Músculos , PoliésteresRESUMO
Postoperative cognitive dysfunction (POCD) is a common neurological system disorder in surgical patients. The choice of anesthetic can potentially reduce POCD. The authors performed this network meta-analysis to compare different anesthetic drugs in reducing the incidence of POCD for elderly people undergoing noncardiac surgery. We searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science for randomized controlled trials comparing the different anesthetic drugs for noncardiac surgery in elderly from inception until July, 2022. The protocol was registered on the PROSPERO database (CRD#42020183014). A total of 34 trials involving 4314 patients undergoing noncardiac surgery in elderly were included. The incidence of POCD for each anesthetic drug was placebo (27.7%), dexmedetomidine (12.9%), ketamine (15.2%), propofol (16.8%), fentanyl (23.9%), midazolam (11.3%), sufentanil (6.3%), sevoflurane (24.0%), and desflurane (28.3%). Pairwise and network meta-analysis showed dexmedetomidine was significantly reducing the incidence of POCD when compared with placebo. Network meta-analysis also suggested dexmedetomidine was significantly reducing the incidence of POCD when compared with sevoflurane. Sufentanil and dexmedetomidine ranked the first and second in reducing the incidence of POCD with the surface under the cumulative ranking curve value of 87.4 and 81.5%. Sufentanil and dexmedetomidine had the greatest possibility to reduce the incidence of POCD for elderly people undergoing noncardiac surgery.
Assuntos
Anestésicos Inalatórios , Dexmedetomidina , Complicações Cognitivas Pós-Operatórias , Humanos , Idoso , Sevoflurano , Anestésicos Inalatórios/uso terapêutico , Dexmedetomidina/uso terapêutico , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Sufentanil/efeitos adversos , Complicações Pós-Operatórias/epidemiologiaRESUMO
Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system after surgery, especially in elderly patients. Many factors can influence POCD, one of which is white matter lesion. Nowadays, stellate ganglion block (SGB) is considered as an effective intervention for postoperative cognitive dysfunction and SIRT1 may play a role in that, but the exact mechanism remains unclear. Therefore, the underlying mechanisms that SGB improves postoperative cognitive dysfunction through SIRT1 in aged rats and its association with white matter lesion are yet to be elucidated. The role of SIRT1 in the process that stellate ganglion block improves the cognitive impairment, and its association with white matter lesion was investigated using splenectomy-induced POCD model. To investigate this result further, we performed transection of the cervical sympathetic trunk on the basis of POCD model, and the role of SIRT1 was then verified again by intraperitoneal injection of EX527 (5 mg/kg) five min before surgery. Data show that SGB treatment has neuroprotective effects in POCD rats. SGB treatment can ameliorate cognitive impairment, neuroinflammation and neuronal apoptosis in white matter. Moreover, SGB treatment enhanced the expression of SIRT1 in the hippocampus and white matter, decreased NF-κB activity in the hippocampus and white matter. It also increased the levels of inflammatory factor in serum and white matter, primarily at the level of anti-inflammatory factor. These findings indicated that SIRT1-mediate white matter repair could be a new therapeutic target for neurodegenerative illnesses.
Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Substância Branca , Ratos , Animais , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Sirtuína 1/metabolismo , Substância Branca/metabolismo , Gânglio Estrelado/metabolismo , Hipocampo/metabolismo , Disfunção Cognitiva/metabolismoRESUMO
Postoperative cognitive dysfunction (POCD) is a common postoperative complication involving the central nervous system, but the underlying mechanism is not well understood. Neuroinflammation secondary to surgery and anesthesia is strongly correlated with POCD. A key aspect of neuroinflammation is microglia activation. Triggering receptor expressed on myeloid cells (TREM)2, which is highly expressed in microglia, is an innate immune receptor that modulates microglia function. In this study we investigated the role of TREM2 in cognitive impairment and microglia-mediated neuroinflammation using a mouse model of POCD and in vitro systems. We found that hippocampus-dependent learning and memory were impaired in POCD mice, which was accompanied by activation of microglia and downregulation of TREM2. Pretreatment with the TREM2 agonist heat shock protein (HSP)60 inhibited surgery-induced microglia activation and alleviated postoperative cognitive impairment. In BV2 microglial cells, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 significantly reversed the attenuation of TREM2 activation on lipopolysaccharide (LPS)-induced neuroinflammation and abrogated the protective effect of activated TREM2 against LPS-induced neuronal injury in a microglia/neuron coculture system. Accordingly, the beneficial effects of TREM2 activation on cognitive function were reversed by preoperative administration of LY294002 in the POCD mouse model. These results demonstrate that TREM2 is involved in the regulation of the inflammatory response mediated by microglia and cognitive impairment following surgery. Activation of TREM2 can attenuate neuroinflammation by modulating PI3K/protein kinase B (Akt) signaling, thereby alleviating postoperative learning and memory deficits.
Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Animais , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia , Doenças Neuroinflamatórias , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Postoperative cognitive decline (POCD) is a common complication after surgery and anesthesia among the elderly. Yet the potential mechanism of POCD remains ambiguous, with limited therapeutic measures currently available. Ketamine has been reported to attenuate POCD after cardiac surgery. Herein, we tried to determine the effect of esketamine (the S-enantiomer of ketamine) on POCD and the possible molecular mechanisms. METHODS: We investigated the effects of esketamine (10 mg/kg) on POCD using an exploratory laparotomy model in aged SD rats (24 months). Open field, novel object recognition, and morris water maze tests were performed on day 30 post-surgery. 24 h or 30 d post-surgery, brain tissue from the hippocampus and ventromedial prefrontal cortex (vmPFC) was harvested and subjected to histopathology and molecular biology analysis. During the in vitro experiment, primary astrocytes from the hippocampus and vmPFC were exposed to lipopolysaccharide (LPS) to investigate the pathological changes in astrocytes during the process of POCD. RESULTS: Our results indicated that exploratory laparotomy could induce significant cognitive and memory decline, accompanied by A2-type astrocytes phenotype loss and increased expression of neuron Aß-42, astrocytes GABA, stimulator of interferon genes (STING) and TANK-binding kinase 1 (TBK1). In addition, LPS exposure significantly decreased the mitochondrial membrane potential and upregulated the level of pyroptosis-associated proteins, including cleaved caspase-1 and IL-18. Notably, treatment with esketamine reversed these abnormalities in vivo and vitro. However, ADU-S100, a special STING activator, suppressed the protective effects of esketamine to a certain extent. Finally, C-176, an antagonist of STING, further enhanced the protective effects of esketamine against POCD. CONCLUSIONS: Findings of our study suggest that esketamine can alleviate surgery-induced POCD in rats via inhibition of the STING/TBK1 signaling pathway.
Assuntos
Disfunção Cognitiva , Ketamina , Complicações Cognitivas Pós-Operatórias , Proteínas Adaptadoras de Transdução de Sinal , Animais , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Interferons/metabolismo , Interferons/farmacologia , Interferons/uso terapêutico , Ketamina/metabolismo , Ketamina/farmacologia , Lipopolissacarídeos/farmacologia , Proteínas de Membrana , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/metabolismo , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Objective: The aim of this study is to investigate the effect of dexmedetomidine on cognitive dysfunction and inflammatory cytokines in the hippocampus after surgery in aged rats. Methods: A total of 30 healthy male Sprague Dawley rats were divided into control group, sham group, and dexmedetomidine group. A splenectomy rat model was established and dexmedetomidine was intraperitoneally injected before operation. The cognitive function of rats was examined by Morris Water-Maze Test, open field experiment, and passive avoidance memory test. And the expression levels of IL-6, IL-1ß, and TNF-α in the hippocampus were examined by ELISA. Results: The escape latency for 5 continuous days in dexmedetomidine group was significantly decreased comparing with control group (all P < 0.05). The number of times of swimming and the percentage of swimming time in dexmedetomidine group were significantly more than those in control group (all P < 0.05). What is more, rats in dexmedetomidine group had the decreased time of stay in the central square and the increased number of standing times in comparison with the control group, and the statistical differences were found (all P < 0.05). Compared with the control group, dexmedetomidine intraperitoneally injected before surgery could significantly inhibit the expression levels of IL-6, IL-1ß, and TNF-α in the hippocampus, and there were statistical differences (all P < 0.05). Conclusion: Dexmedetomidine could significantly relieve the postoperative cognitive dysfunction in aged rats. The mechanism may be associated with the decreased inflammatory cytokines in the hippocampus.
Assuntos
Dexmedetomidina , Complicações Cognitivas Pós-Operatórias , Animais , Citocinas , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/análise , Masculino , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismoRESUMO
RATIONALE: Due to its anti-inflammatory effect, dexmedetomidine (DEX) can confer neuroprotection in postoperative neurocognitive disorders (NCD). Here, the mechanism responsible for this effect of DEX is rarely ascertained. OBJECTIVES: Our research was implemented to figure out mechanism governing the protection of DEX against hippocampal neuroinflammation in postoperative NCD. METHODS: Exploratory laparotomy was applied for generating a postoperative NCD mouse model before bilateral hippocampal injection with microRNA (miR)-329-3p-agomir and intraperitoneal injection with DEX. Cognitive function of mice was evaluated by water maze test and fear conditioning test. Immunofluorescence was performed to assess microglial activation in hippocampus. After cell transfection and DEX treatment, mouse microglial cells (BV-2) were stimulated by lipopolysaccharide (LPS). IL-1ß, IL-6, and TNF-α levels and the number of phagocytes were assessed by ELISA and flow cytometry. Dual-luciferase reporter assay was adopted to assess the relationship between miR-329-3p and CREB1. RESULTS: miR-329-3p expression was reduced in the postoperative NCD mice after DEX treatment. DEX treatment or miR-329-3p downregulation caused attenuated cognitive dysfunction and microglia activation as well as reduced IL-1ß, IL-6, and TNF-α levels in the hippocampus of the postoperative NCD mice. Mechanistically, miR-329-3p inversely targeted CREB1 that activated IL1RA in LPS-induced BV-2 cells. DEX treatment, miR-329-3p inhibition, or CREB1 or IL1RA upregulation curtailed the release of proinflammatory proteins and the number of phagocytes in LPS-induced BV-2 cells. CONCLUSIONS: Collectively, our data provided the novel insight of the neuroprotective mechanism of DEX in postoperative NCD pertaining to the miR-329-3p/CREB1/IL1RA axis.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Dexmedetomidina , Proteína Antagonista do Receptor de Interleucina 1 , MicroRNAs , Doenças Neuroinflamatórias , Complicações Cognitivas Pós-Operatórias , Animais , Dexmedetomidina/metabolismo , Dexmedetomidina/uso terapêutico , Hipocampo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , MicroRNAs/genética , Doenças Neuroinflamatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Anesthesia and surgery are likely causing cognitive dysfunction in patients, especially the elderly. However, the underlying pathogenic mechanisms largely remain unclear. Accumulating evidence suggest that signaling between Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in the pathogenesis and treatment of brain dysfunction, while sulforaphane (SFN), a natural compound acting as an Nrf2 agonist, can improve brain function. In the present study, we used 9-month-old mice to perform tibial fracture surgery under isoflurane general anesthesia. Hierarchical cluster analysis of Morris water maze test (MWMT) analysis was performed to classify mice into post-operative cognitive dysfunction (POCD) versus non-POCD phenotypes. Expression levels of Keap1 and Nrf2 were significantly decreased in the medial prefrontal cortex (mPFC), hippocampus and liver, but not in the nucleus accumbens, muscle and gut of POCD mice compared to control and non-POCD mice. Interestingly, both pretreatment and posttreatment with SFN significantly improved the abnormal behaviors of mice in the MWMT, in parallel with the up-regulated levels of Keap1-Nrf2 signaling in the mPFC, hippocampus and liver. In conclusion, these results suggest that decreased Keap1-Nrf2 signaling in the mPFC, hippocampus and liver may contribute to the onset of POCD, and that SFN exerts facilitating effects on POCD symptoms by increasing Keap1-Nrf2 signaling.
Assuntos
Anestesia Geral/efeitos adversos , Hipocampo/efeitos dos fármacos , Isotiocianatos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Nootrópicos/farmacologia , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Sulfóxidos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/agonistas , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate whether a low-dose perioperative infusion of Dex reduces early POCD. DESIGN: This study was a double-blind, randomized, placebo-controlled trial that randomly assigned patients to Dex or saline placebo infused during surgery and patient-controlled intravenous analgesia (PCIA) infusion. Patients were assessed for postoperative cognitive decline. Interventions. Dex was infused at a loading dose of 0.5 µg/kg intravenously (15 min after entering the operation room) followed by a continuous infusion at a rate of 0.5 µg/kg/h until one-lung ventilation or artificial pneumothorax ended. Patients in the Dex group received regular PCIA pump with additional dose of Dex (200 µg). RESULTS: In total, 126 patients were randomized, and 102 patients were involved in the result analysis. The incidence of POCD was 36.54% (19/52) in the Dex group and 32.00% (16/50) in the normal saline (NS) group, with no statistic difference. No significant difference was observed between the two groups in terms of Telephone Interview for Cognitive Status-Modified (TICS-m) scores at different times. However, the TICS-m score at 7 days after surgery was significantly lower than that at 30 days in 102 patients (32.93 ± 0.42 vs. 33.92 ± 0.47, P = 0.03). The visual analogue scale scores in the Dex group were significantly lower than those in the NS group 1 day postoperation at rest and activity (2.00 [1.00-3.00] vs. 3.00 [2.00-4.00], P < 0.01; 4.00 [3.00-5.00] vs. 5.00 [4.00-6.00], P < 0.05, respectively). Patients receiving Dex or NS had no statistical difference in activities of daily living (ADLs) scores at 7 and 30 days after surgery, but the ADL score at 30 days after surgery showed a significant reduction compared with that at 7 days (P < 0.01). Patients in the Dex group had a shorter hospital length of stay (15.26 ± 3.77 vs. 17.69 ± 5.09, P = 0.02) and less expenses (52458.71 ± 10649.30 vs. 57269.03 ± 9269.98, P = 0.04) than those in the NS group. CONCLUSIONS: Low-dose Dex in the perioperative period did not reduce the incidence of early POCD in thoracic surgery. However, it relieved postoperative pain, decreased the hospitalization expenses, and shortened the length of stay.
Assuntos
Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Atividades Cotidianas , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Idoso , Analgesia Controlada pelo Paciente , Analgésicos não Narcóticos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Período Perioperatório , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/psicologia , Estudos ProspectivosRESUMO
BACKGROUND: Inflammation is considered a key factor in the development of postoperative cognitive dysfunction (POCD). Therefore, we hypothesized that pre-operative anti-inflammatory treatment with ibuprofen would inhibit POCD in our rat-model. METHODS: Male Wistar rats of 3 or 23 months old received a single injection of ibuprofen (15 mg/kg i.p.) or were control handled before abdominal surgery. Timed blood and fecal samples were collected for analyses of inflammation markers and gut microbiome changes. Behavioral testing was performed from 9 to 14 days after surgery, in the open field, novel object- and novel location-recognition tests and Morris water maze. Neuroinflammation and neurogenesis were assessed by immune histochemistry after sacrifice on postoperative day 14. RESULTS: Ibuprofen improved short-term spatial memory in the novel location recognition test, and increased hippocampal neurogenesis. However, these effects were associated with increased hippocampal microglia activity. Whereas plasma cytokine levels (IL1-ß, IL6, IL10, and TNFα) were not significantly affected, VEGF levels increased and IFABP levels decreased after ibuprofen. Long-term memory in the Morris water maze was not significantly improved by ibuprofen. The gut microbiome was neither significantly affected by surgery nor by ibuprofen treatment. In general, effects in aged rats appeared similar to those in young rats, though less pronounced. CONCLUSION: A single injection of ibuprofen before surgery improved hippocampus-associated short-term memory after surgery and increased neurogenesis. However, this favorable outcome seemed not attributable to inhibition of (neuro)inflammation. Potential contributions of intestinal and blood-brain barrier integrity need further investigation. Although less pronounced compared to young rats, effects in aged rats indicate that even elderly individuals could benefit from ibuprofen treatment.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Cognição/efeitos dos fármacos , Ibuprofeno/administração & dosagem , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Cuidados Pré-Operatórios/métodos , Animais , Cognição/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Complicações Cognitivas Pós-Operatórias/metabolismo , Complicações Cognitivas Pós-Operatórias/psicologia , Ratos , Ratos WistarRESUMO
Postoperative cognitive dysfunction (POCD; cognitive change associated with anesthesia and surgery) is one of the most serious long-term postoperative complications that occur in elderly patients. Dexmedetomidine (DEX) has been shown to be beneficial for improving outcomes of postoperative cognitive function. However, the exact mechanism underlying this role requires is yet to be found. The present study aims to determine the pathways involved in the protective effects of DEX against POCD in C57BL/6 J aged mice. DEX was administered after POCD modeling in C57BL/6 J aged mice. The cognitive function was evaluated after DEX treatment using novel object recognition, open field, and Y-maze tests. We also assessed its effects on neuron apoptosis and production of TNF-α and IL-1ß in mouse brain tissues as well as expression levels of DNA damage-related proteins p53, p21, and γH2AX. Interactions between early growth response 1 (EGR1) and p53, microRNA (miR)-381, and EGR1 were identified by ChIP and luciferase reporter assays, and gain- and loss-of-function experiments were performed to confirm the involvement of their interaction in POCD. DEX administration attenuated hippocampal neuron apoptosis, neuroinflammation, DNA damage, and cognitive impairment in aged mice. miR-381 targeted EGR1 and disrupted its interaction with p53, leading to a decline in hippocampal neuron apoptosis, DNA damage, neuroinflammation, and cognitive impairment. Furthermore, DEX administration resulted in the enhancement of miR-381 expression and the subsequent inhibition of EGR1/p53 to protect against cognitive impairment in aged mice. Overall, these results indicate that DEX may have a potential neuroprotective effect against POCD via the miR-381/EGR1/p53 signaling, shedding light on the mechanisms involved in neuroprotection in POCD.
Assuntos
Dexmedetomidina/uso terapêutico , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Hipocampo/metabolismo , MicroRNAs/metabolismo , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Complicações Cognitivas Pós-Operatórias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Dexmedetomidina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Complicações Cognitivas Pós-Operatórias/psicologia , Proteína Supressora de Tumor p53/antagonistas & inibidoresRESUMO
Neuroinflammation and oxidative stress coexist and interact in the progression of postoperative cognitive dysfunction (POCD) and other neurodegenerative disease. Mounting studies reveal that Dexmedetomidine (Dex) possesses anti-inflammatory and antioxidant properties. Nevertheless, whether Dex exerts neuroprotective effect on the cognitive sequelae of oxidative stress and inflammatory process remains unclear. A mouse model of abdominal exploratory laparotomy-induced cognitive dysfunction was employed to explore the underlying mechanism of neuroprotective effects exerted by Dex in POCD. Aged mice were treated with Dex (20 µg/kg) 20 min prior to surgery. Open field test (OFT) and Morris water maze (MWM) were employed to examine the cognitive function on postoperative day 3 (POD 3) or POD 7. In the present study, mice underwent surgery exhibited cognitive impairment without altering spontaneous locomotor activity, while the surgery-induced cognitive impairment could be alleviated by Dex pretreatment. Dex inhibited surgery-induced pro-inflammatory cytokines accumulation and microglial activation in the hippocampi of mice. Furthermore, Dex decreased MDA levels, enhanced SOD activity, modulated CDK5 activity and increased BDNF expression in the hippocampus. In addition, Dex remarkably reduced the surgery-induced increased ratio of Bax/Bcl-2 and apoptotic neurons in the hippocampi of aged mice. Collectively, our study provides evidence that Dex may exert neuroprotective effects against surgery-induced cognitive impairment through mechanisms involving its anti-inflammatory and antioxidant properties, as well as the suppression on the mitochondrial permeability transition pore and apoptosis-related pathway.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Dexmedetomidina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Complicações Cognitivas Pós-Operatórias/tratamento farmacológico , Abdome/cirurgia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Teste de Campo Aberto/efeitos dos fármacos , Complicações Cognitivas Pós-Operatórias/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Post-operative cognitive dysfunction (POCD) is a debilitating clinical phenomenon in elderly patients. Management of pain in elderly is complicated because analgesic opiates elicit major side effects. In contrast, paracetamol (acetaminophen) has shown analgesic efficacy, no impact on cognition, and its side effects are well tolerated. We investigated the efficacy of paracetamol, compared to the opioid analgesic buprenorphine, in a model of POCD by investigating cognitive decline, allodynia, peripheral and hippocampal cytokines levels, and hippocampal microtubule dynamics as a key modulator of synaptic plasticity. A POCD model was developed in middle-aged (MA) rats by inducing a tibia fracture via orthopaedic surgery. Control MA rats did not undergo any surgery and only received isoflurane anaesthesia. We demonstrated that cognitive decline and increased allodynia following surgery was prevented in paracetamol-treated animals, but not in animals which were exposed to anesthesia alone or underwent the surgery and received buprenorphine. Behavioral alterations were associated with different peripheral cytokine changes between buprenorphine and paracetamol treated animals. Buprenorphine showed no central effects, while paracetamol showed modulatory effects on hippocampal cytokines and markers of microtubule dynamics which were suggestive of neuroprotection. Our data provide the first experimental evidence corroborating the use of paracetamol as first-choice analgesic in POCD.