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Wang J, Gao S, Fu S, Li Y, Su L, Li X, Wu G, Jiang J, Zhao Z, Yang C, Wang X, Cui K, Sun X, Qi X, Wang C, Sun H, Shao S, Tian Y, Gong T, Luo J, Zheng J, Cui S, Liao F, Liu F, Wang D, Wong CCL, Yi M, Wan Y. Irisin reprograms microglia through activation of STAT6 and prevents cognitive dysfunction after surgery in mice. Brain Behav Immun 2025; 125:68-91. [PMID: 39701329 DOI: 10.1016/j.bbi.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 12/09/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024] Open
Abstract
Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction.
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Affiliation(s)
- Jiaxin Wang
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Shuaixin Gao
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China; Human Nutrition Program, Department of Human Sciences & James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Su Fu
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Yawei Li
- Department of Anesthesiology, Peking University First Hospital, Beijing 10034, China
| | - Li Su
- Peking University Medical and Health Analysis Center, Peking University, Beijing 10034, China
| | - Xiaoman Li
- Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Guanghao Wu
- School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, China
| | - Jiankuo Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Zifang Zhao
- Department of Pain Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Chaojuan Yang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing 100191, China
| | - Xiaoyi Wang
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Kun Cui
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China; Beijing Life Science Academy, Beijing 102209, China
| | - Xiaoyan Sun
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Xuetao Qi
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Cheng Wang
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China; Changping Laboratory, Beijing 102206, China
| | - Haojie Sun
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China; UCL School of Pharmacy, University College London, London WC1N 1AX, UK
| | - Shan Shao
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Yue Tian
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Tingting Gong
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Jianyuan Luo
- Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing 100191, China
| | - Jie Zheng
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Shuang Cui
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Feifei Liao
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China
| | - Fengyu Liu
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China.
| | - Dongxin Wang
- Department of Anesthesiology, Peking University First Hospital, Beijing 10034, China.
| | - Catherine C L Wong
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
| | - Ming Yi
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China; Medical Innovation Center (Taizhou) of Peking University, Taizhou 225316, China.
| | - You Wan
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Beijing, 100191, China; Medical Innovation Center (Taizhou) of Peking University, Taizhou 225316, China.
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Chen T, Zhang B, Zhang X, Tang L, Wang C. Electroacupuncture improves postoperative cognitive dysfunction by inhibiting ferroptosis via the TFR1-DMT1-FPN pathway. Acupunct Med 2025:9645284241302816. [PMID: 39754452 DOI: 10.1177/09645284241302816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
OBJECTIVE The aim of this study was to investigate the role of ferroptosis in the occurrence of postoperative cognitive dysfunction (POCD) using a mouse model and to elucidate whether electroacupuncture (EA) can improve POCD by suppressing ferroptosis via the transferrin receptor 1 (TFR1)-divalent metal transporter 1 (DMT1)-ferroportin (FPN) pathway. METHODS The experiment involved three groups: the control group, the POCD group and the POCD + EA group. The POCD animal model was established using sevoflurane anesthesia and tibial fracture. Cognitive and behavioral changes in mice were assessed using the novel object recognition test (NORT) and the Morris water maze (MWM) test, 1 and 3 days after surgery. Transmission electron microscopy was performed to observe changes in the mitochondrial structure of hippocampal tissue. Enzyme-linked immunosorbent assay was conducted to determine the levels of glutathione (GSH) and iron ion (Fe) concentrations. Western blot analysis was used to measure the expression of TFR1, DMT1 and iron pump protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to detect the mRNA levels of DMT1 and FPN. RESULTS Based on the experimental results of the MWM test and the NORT, we found that EA can improve POCD in mice. Observation by projection electron microscopy showed that EA improved the mitochondrial structure in the hippocampus. The enzyme-linked immunosorbent assay (ELISA) results showed that EA suppressed ferroptosis in the hippocampal area. The qRT-PCR and Western blot results suggested that EA suppresses ferroptosis by regulating the TFR1-DMT1-FPN pathway. CONCLUSION This study reveals that sevoflurane and tibial fractures cause cognitive damage through the mechanism of ferroptosis, while EA may inhibit ferroptosis through the TFR1-DMT1-FPN pathway and improve POCD when induced in this way.
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Affiliation(s)
- Tianren Chen
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Binsen Zhang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaojia Zhang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Lu Tang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Chunai Wang
- Gansu Province Hospital of Traditional Chinese Medicine, Lanzhou, China
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Cascella M, Miranda B, Gagliardi C, Santaniello L, Mottola M, Mancusi A, Ferrara L, Monaco F, Gargano F, Perri F, Ottaiano A, Capuozzo M, Piazza O, Pepe S, Crispo A, Guida A, Salzano G, Varrassi G, Liguori L, Sabbatino F, The TRIAL Group. Dissecting the link between PD-1/PD-L1-based immunotherapy and cancer pain: mechanisms, research implications, and artificial intelligence perspectives. EXPLORATION OF IMMUNOLOGY 2024:802-821. [DOI: 10.37349/ei.2024.00174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 11/01/2024] [Indexed: 02/02/2025]
Abstract
Cancer-related pain represents one of the most common complaints of cancer patients especially for those with advanced-stage of disease and/or bone metastases. More effective therapeutic strategies are needed not only to improve the survival of cancer patients but also to relieve cancer-related pain. In the last decade, immune checkpoint inhibitor (ICI)-based immunotherapy targeting programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) has revolutionized cancer care. Beyond its anticancer role, PD-1/PD-L1 axis pathway is involved in many other physiological processes. PD-L1 expression is found in both malignant tissues and normal tissues including the dorsal root ganglion, and spinal cord. Through its interaction with PD-1, PD-L1 can modulate neuron excitability, leading to the suppression of inflammatory, neuropathic, and bone cancer pain. Therefore, since the intricate relationship between immunotherapy and pain should be largely dissected, this comprehensive review explores the complex relationship between PD-1/PD-L1-based immunotherapy and cancer-related pain. It delves into the potential mechanisms through which PD-1/PD-L1 immunotherapy might modulate pain pathways, including neuroinflammation, neuromodulation, opioid mechanisms, and bone processes. Understanding these mechanisms is crucial for developing future research directions in order to optimize pain management strategies in cancer patients. Finally, this article discusses the role of artificial intelligence (AI) in advancing research and clinical practice in this context. AI-based strategies, such as analyzing large datasets and creating predictive models, can identify patterns and correlations between PD-1/PD-L1 immunotherapy and pain. These tools can assist healthcare providers in tailoring treatment plans and pain management strategies to individual patients, ultimately improving outcomes and quality of life for those undergoing PD-1/PD-L1-based immunotherapy.
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Affiliation(s)
- Marco Cascella
- Anesthesia and Pain Management, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Brigida Miranda
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Carmen Gagliardi
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Lucia Santaniello
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Milena Mottola
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Alida Mancusi
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Laura Ferrara
- Anesthesia and Pain Management, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Federica Monaco
- Unit of Anesthesia, ASL Napoli 1 Centro, 80145 Naples, Italy
| | - Francesca Gargano
- Anesthesia and Intensive Care, U.O.C. Fondazione Policlinico Campus Bio-Medico, 00128 Roma, Italy
| | - Francesco Perri
- Medical and Experimental Head and Neck Oncology Unit, Istituto Nazionale Tumori Di Napoli, IRCCS “G. Pascale”, 80131 Naples, Italy
| | - Alessandro Ottaiano
- Unit of Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori Di Napoli, IRCCS “G. Pascale”, 80131 Naples, Italy
| | | | - Ornella Piazza
- Anesthesia and Pain Management, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Stefano Pepe
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Anna Crispo
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori Di Napoli, IRCCS “G. Pascale”, 80131 Naples, Italy
| | - Agostino Guida
- U.O.C. Odontostomatologia, A.O.R.N. A. Cardarelli, 80131 Naples, Italy
| | - Giovanni Salzano
- Maxillofacial Surgery Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80138 Naples, Italy
| | - Giustino Varrassi
- Department of Research, Fondazione Paolo Procacci, 00193 Rome, Italy
| | - Luigi Liguori
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - The TRIAL Group
- The TRIAL (Try to Research and to Improve the Anticancer Links) Group, 82100 Benevento, Italy
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Kong X, Lyu W, Lin X, Lin C, Feng H, Xu L, Shan K, Wei P, Li J. Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis. J Neuroinflammation 2024; 21:104. [PMID: 38649932 PMCID: PMC11034021 DOI: 10.1186/s12974-024-03103-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/17/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.
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Affiliation(s)
- Xiangyi Kong
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Wenyuan Lyu
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Xiaojie Lin
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Chunlong Lin
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Hao Feng
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Lin Xu
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Kaiyue Shan
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China
| | - Penghui Wei
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China.
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China.
| | - Jianjun Li
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China.
- Laboratory of Anesthesia and Brain Function, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, China.
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Hu L, Kang S, Peng Q, An E, Lu J, Yang H, Zhou H, Zhang B. Knowledge, attitudes, and practice toward postoperative cognitive dysfunction among anesthesiologists in China: a cross-sectional study. BMC MEDICAL EDUCATION 2024; 24:359. [PMID: 38561709 PMCID: PMC10986038 DOI: 10.1186/s12909-024-05358-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 03/27/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND To investigate the knowledge, attitudes, and practice (KAP) toward postoperative cognitive dysfunction (POCD) among anesthesiologists in China. METHODS This cross-sectional study was conducted nationwide among Chinese anesthesiologists between December 2022 and January 2023. The demographic information and KAP scores of the respondents were collected using a web-based questionnaire. The mean KAP dimension scores ≥ 60% were considered good. RESULTS This study enrolled 1032 anesthesiologists (51.2% male). The mean total scores of knowledge, positive attitude, and positive practice were 9.3 ± 1.2 (max 12), 34.8 ± 3.3 (max 40), and 30.6 ± 6.7 (max 40), respectively. The knowledge items with correctness scores < 60% were "the anesthetic drugs that tend to cause POCD" (23.3%) and "Treatment of POCD" (40.3%). Multivariable analysis showed that ≥ 40 years old, master's degree or above, intermediate professional title (i.e., attending physician), senior professional title (i.e., chief physician), and working in tertiary hospitals were independently associated with adequate knowledge. Multivariable analysis showed that the attitude scores, middle professional title, and ≥ 16 years of experience were independently associated with good practice. CONCLUSIONS These results suggest that Chinese anesthesiologists have good knowledge, favorable attitudes, and good practice toward POCD. Still, some points remain to be improved (e.g., the drugs causing POCD and managing POCD) and should be emphasized in training and continuing education. TRIAL REGISTRATION ChiCTR2200066749.
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Affiliation(s)
- Li Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Shuai Kang
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Qiaoyi Peng
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Erdan An
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jian Lu
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hao Yang
- Department of Anesthesiology, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Hongmei Zhou
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
| | - Bin Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
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Liu T, Chen T, Gong J, You C, Zhang B, Luo C, Liu Z, Chen C. The effect of TEMPOL pretreatment on postoperative cognitive function, inflammatory response, and oxidative stress in aged rats under sevoflurane anesthesia. Immun Inflamm Dis 2023; 11:e1023. [PMID: 37773699 PMCID: PMC10538358 DOI: 10.1002/iid3.1023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 08/29/2023] [Accepted: 09/09/2023] [Indexed: 10/01/2023] Open
Abstract
INTRODUCTION The heterocyclic compound 4-hydroxy-(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPOL) has a protective effect on neurological function in brain tissues damaged by ischemia and hypoxia. This study explored the effects of TEMPOL pretreatment on postoperative cognitive function in aged rats under sevoflurane anesthesia, focusing on inflammatory response and oxidative stress. METHODS Sixty male rats were divided into normal control (C), sevoflurane anesthesia (S), TEMPOL pretreatment (T), and sevoflurane anesthesia + TEMPOL pretreatment (ST) groups (15 per group). Groups T and ST rats received continuous intraperitoneal TEMPOL (100 mg/kg) for 3 days, while groups C and S rats were injected with 0.9% saline. After pretreatment, groups S and ST received 3% sevoflurane anesthesia. RESULTS Rats in group S exhibited a longer swimming distance, longer escape latency, lower frequency of platform crossing, and shorter dwell time in the targeted quadrant than those in groups C and T. Rats in group ST exhibited a shorter swimming distance, shorter escape latency, higher frequency of platform crossing, and longer dwell time in the targeted quadrant than those in group S. The expressions of interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase, and Ym1/2 messenger ribonucleic acid were higher in groups S and ST rats than in groups C and T rats and lower in group ST rats than in group S rat (p < .05). Superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) were lower, while malondialdehyde (MDA) was higher in groups S and ST rats than in groups C and T rats (p < .05). Group ST showed higher SOD, T-AOC, and GSH-Px, and lower MDA than group S (p < .05). CONCLUSIONS TEMPOL pretreatment attenuated postoperative cognitive impairment induced by sevoflurane anesthesia in aged rats. This may be attributed to the downregulation of NR2B-CREB-BDNF pathway, reducing the inflammatory response and oxidative stress damage in hippocampal tissue.
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Affiliation(s)
- Tianpin Liu
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
| | - Tianzi Chen
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
| | - Jianhua Gong
- Department of Hepatobiliary and Pancreatic Surgery, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of Hepatobiliary and Pancreatic SurgeryYichang Central People's HospitalYichangHubeiChina
| | - Changchang You
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
| | - Bo Zhang
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
| | - Caiyun Luo
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
| | - Zhigui Liu
- Department of AnesthesiologyThe Affiliated Hospital of Guilin Medical UniversityGuilinGuangxiChina
| | - Chun Chen
- Department of Anesthesiology, The First College of Clinical Medical ScienceChina Three Gorges UniversityYichangHubeiChina
- Department of AnesthesiologyYichang Central People's HospitalYichangHubeiChina
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Wang F, Hao X, Zhu Y. Effects of perioperative intravenous glucocorticoids on perioperative neurocognitive disorders in adults after surgery: A PRISMA-compliant meta-analysis of randomized controlled trials. Medicine (Baltimore) 2023; 102:e34708. [PMID: 37653739 PMCID: PMC10470771 DOI: 10.1097/md.0000000000034708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Randomized controlled trials (RCTs) have shown uncertain clinical benefits from perioperative intravenous glucocorticoids for perioperative neurocognitive disorders (PND). Thus, this meta-analysis was performed to evaluate whether perioperative intravenous glucocorticoids can decrease the occurrence of PND among adults undergoing surgery. METHODS We searched 4 databases (MEDLINE, Embase, CENTRAL and Web of Science) for RCTs that assessed the incidence of PND in adults (aged ≥ 18 years old) after surgery. Two reviewers independently assessed the studies for eligibility, extracted data, and assessed the risk of bias in each study. We assessed the certainty of evidence using GRADEpro software. RESULTS A total of 10 studies (N = 14,967) were eligible. Compared with controls, glucocorticoids were not associated with reducing the risk of postoperative cognitive dysfunction (POCD) (risk ratio [RR]: 0.79 95% confidence interval [CI]: 0.41-1.55, P = .50, I2 = 85%), risk of postoperative delirium (POD) (RR: 0.87 95% CI: 0.74-1.03, P = .10, I2 = 36%), the length of stay in intensive care unit (ICU) (mean difference [MD] -0.21 95% CI: -1.20 to 0.79, P = .68, I2 = 84%), 30-day mortality (RR: 0.92 95% CI: 0.59-1.46, P = .73, I2 = 0%), or postoperative atrial fibrillation (RR: 0.94 95% CI: 0.86-1.01, P = .11, I2 = 25%). However, there was significant difference between glucocorticoids and control group in the length of hospital stay (LOS) (MD: -0.39 95% CI: -0.62 to -0.16, P = .001, I2 = 0%), and postoperative infections (RR: 0.65 95% CI: 0.56-0.76, P < .00001, I2 = 0%). CONCLUSIONS Perioperative intravenous glucocorticoids did not reduce the risk of PND in adults after surgery but might be associated with shorter the LOS and lower the incidence of postoperative infections. More, larger, higher-quality RCTs including neurological surgery or hip fracture surgery and different doses of glucocorticoids compared with placebos are needed to explore the intervention effects.
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Affiliation(s)
- Fei Wang
- Department of Anesthesiology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuechao Hao
- Department of Anesthesiology, West China Hospital of Sichuan University; Research Units of Perioperative Stress Assessment and Clinical Decision (2018RU012), Chinese Academy of Medical Sciences, Chengdu, China
| | - Yihao Zhu
- Department of Anesthesiology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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Bhuiyan P, Sun Z, Chen Y, Qian Y. Peripheral surgery triggers mast cells activation: Focusing on neuroinflammation. Behav Brain Res 2023; 452:114593. [PMID: 37499912 DOI: 10.1016/j.bbr.2023.114593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/12/2023] [Accepted: 07/20/2023] [Indexed: 07/29/2023]
Abstract
Peripheral surgery can lead to a systemic aseptic inflammatory response comprising several mediators aiming at restoring tissue homeostasis. It induces inflammatory mechanisms through neuroimmune interaction between the periphery and to brain which also plays a critical role in causing cognitive impairments. Accumulating scientific evidence revealed that acute neuroinflammation of the brain triggered by peripheral surgery that causes peripheral inflammation leads to transmitting signals into the brain through immune cells. Mast cells (MCs) play an important role in the acute neuroinflammation induced by peripheral surgical trauma. After peripheral surgery, brain-resident MCs can be rapidly activated followed by releasing histamine, tryptase, and other inflammatory mediators. These mediators then interact with other immune cells in the peripheral and amplify the signal into the brain by disrupting BBB and activating principle innate immune cells of brain including microglia, astrocytes, and vascular endothelial cells, which release abundant inflammatory mediators and in turn accelerate the activation of brain MCs, amplify the cascade effect of neuroinflammatory response. Surgical stress may induce HPA axis activation by releasing corticotropin-releasing hormone (CRH) subsequently influence the activation of brain MCs, thus resulting in impaired synaptic plasticity. Herein, we discuss the better understating of MCs mediated neuroinflammation mechanisms after peripheral surgery and potential therapeutic targets for controlling inflammatory cascades.
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Affiliation(s)
- Piplu Bhuiyan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China
| | - Zhaochu Sun
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China
| | - Yinan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
| | - Yanning Qian
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
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Hsiao WJ, Chen CY, Kang YN, Hu CJ, Chen CH, Lin PL, Lin YC. Apolipoprotein E4 allele is genetically associated with risk of the short- and medium-term postoperative cognitive dysfunction: A meta-analysis and trial sequential analysis. PLoS One 2023; 18:e0282214. [PMID: 36827351 PMCID: PMC9955600 DOI: 10.1371/journal.pone.0282214] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
The aim of systematic review and meta-analysis was to investigate whether APOE4 was associated with postoperative neurologic dysfunction occurrence in short- or medium-term among surgical patients and to study the potential genetic association among these two entities. We searched electronic databases for reserch studies to evaluate the association of APOE4 with postoperative delirium (POD) or short- and medium term postoperative cognitive dysfunction (POCD). Twenty-two trials (16 prospective and six retrospective) with 6734 patients were included. APOE4 alleles was shown significantly associated with POCD within 1 week (odds ratio, OR, 1.89, 95% confidence interval, CI, 1.36 to 2.6278, p < 0.01) in the random-effects model. A significant association was also noted between APOE4 and POCD in medium-term, 1-3 months, after surgery (OR: 1.67, 95% CI: 1.003-2.839, p = 0.049). However, APOE4 was not significantly associated with POCD 1 year after surgery (OR: 0.98, 95% CI: 0.57-1.70, p = 0.9449) and POD (OR: 1.28, 95% CI: 0.85-1.91, p = 0.23). In conclusion, APOE4 alleles was genetically associated with short- and medium-term postoperative neurological dysfunction and future screening or preventive strategies derived is highly potential to improve outcomes.
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Affiliation(s)
- Wei-Jen Hsiao
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chien-Yu Chen
- Department of Anesthesia, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Anesthesia, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Humanities in Medicine, College of Humanities and Social Sciences, Taipei Medical University, Taipei, Taiwan
| | - Yi-No Kang
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei City, Taiwan
- Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei City, Taiwan
| | - Chaur-Jong Hu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, California, United States of America
| | - Pei-Lin Lin
- Department of Anesthesia, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Cih Lin
- Department of Anesthesia, Taipei Medical University Hospital, Taipei, Taiwan
- School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan
- Post-Baccalaureate Program in Nursing, College of Nursing, Taipei Medical University, Taipei City, Taiwan
- * E-mail:
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Fan X, Zhao Z, Huang Z, Wu M, Wang D, Xiao J. Mineralocorticoid receptor agonist aldosterone rescues hippocampal neural stem cell proliferation defects and improves postoperative cognitive function in aged mice. World J Biol Psychiatry 2023; 24:149-161. [PMID: 35615969 DOI: 10.1080/15622975.2022.2082524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Hippocampal neurogenesis is closely related to learning and memory, and hippocampal neurogenesis disorders are involved in the development of many neurodegenerative diseases. Mineralocorticoid receptor (MR) plays a vital role in regulating stress response, neuroendocrine and cognitive functions, and is involved in regulating the integrity and stability of neural networks. However, the potential role of MR in the pathogenesis of postoperative cognitive dysfunction (POCD) is unclear. Therefore, this study evaluated the effect and mechanism of MR activation on postoperative hippocampal neurogenesis and cognitive function in aged mice. METHODS 18-month-old male Kunming mice were randomly divided into Control group (C group), Surgery group (S group), Surgery+ Aldosterone group (S+Aldo group), Surgery + Wortmannin group (S+Wort group), Surgery + Aldosterone + Wortmannin group (S+Aldo+Wort group). Laparotomy was used to establish an animal model of postoperative cognitive dysfunction. After surgery, mice were intraperitoneally injected with aldosterone (100 ug/kg,150 ug/kg,200 ug/kg) and / or wortmannin (1 mg/kg); One day before the sacrifice, mice were injected intraperitoneally with BrdU (100 mg / kg / time, 3 times in total). Mice were subjected to Morris water maze and field tests at 1, 3, 7, and 14 days after surgery. Immunofluorescence was used to detect the number of BrdU +, Nestin +, BrdU/Nestin + positive cells in the hippocampal dentate gyrus of mice at 1, 3, 7 and 14 days after surgery. Western-blot was used to detect PI3K/Akt/GSK-3β signaling pathway related proteins Akt, p-Akt, GSK-3β, P-GSK-3β expression. RESULTS Stress impairs the performance of aged mice in water maze and open field tests, reduces the number of BrdU/Nestin+ cells in the hippocampal dentate gyrus, and inhibits the phosphorylation of Akt and GSK-3β proteins in the hippocampus. Aldosterone treatment promotes P-Akt, P-GSK-3β protein expression and hippocampal neural stem cell proliferation, and improves postoperative cognitive dysfunction. However, wortmannin treatment significantly reversed these effects of aldosterone. CONCLUSIONS The mineralocorticoid receptor agonist aldosterone promotes the proliferation of hippocampal neural stem cells and improves cognitive dysfunction in aged mice after surgery, and the mechanism may be related to activation of PI3K/Akt/GSK-3β signaling.
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Affiliation(s)
- Xuhong Fan
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China
| | - Zhenyu Zhao
- Department of Anesthesiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Zixia Huang
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China
| | - Mingyue Wu
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China
| | - Deming Wang
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China
| | - Ji Xiao
- Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China
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11
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Luo TY, Zhou W, Xiang GF, Zhang Y, Liu Q. Identification of perioperative neurocognitive dysfunction biomarkers in cerebrospinal fluid with quantitative proteomic approach in patients undergoing transurethral resection of prostate with combined spinal and epidural analgesia. Medicine (Baltimore) 2022; 101:e30448. [PMID: 36086739 PMCID: PMC10980413 DOI: 10.1097/md.0000000000030448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 07/29/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND This study aimed to identify predictive biomarkers of perioperative neurocognitive dysfunction (PND) in cerebrospinal fluid of elderly male patients undergoing elective transurethral resection of prostate, using an isobaric tags for relative and absolute quantitative-based quantitative proteomic approach. METHODS Patients were evaluated with Mini Mental State Examination at -1 and+3 days of operation. Presence of PND was determined with Z-score method. Patients characteristics and quantitative cerebrospinal fluid proteomes detected with isobaric tags for relative and absolute quantitative-were compared between PND and non-PND patients. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were performed to identify pathways potentially involved in PND. RESULT A total of 229 patients were included in the study and 32 were diagnosed with PND (incidence 14.4%). The age, incidence of hypertension, and diabetes of PND patients were significantly higher than non-PND patients (P < .05). There were 85 differentially expressed proteins identified, among which High Mobility Group Box 1, prostaglandin D synthase, and matrix metalloproteinase inhibitor were considered to be promising candidates as they might play important roles in pathophysiology of PND. CONCLUSION Proteomic approach identified potential biomarkers for predicting the occurrence of PND. These findings need to be validated in further studies.
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Affiliation(s)
- Tian-Yan Luo
- Department of Anesthesiology, Hospital (t.c.m) affiliated to southwest medical university, Luzhou, China
| | - Wei Zhou
- Department of Urology, Hejiang Hospital of Traditional Chinese Medicine, Luzhou, China
| | - Gui-Fang Xiang
- Department of Anesthesiology, Hejiang Hospital of Traditional Chinese Medicine, Luzhou, China
| | - Ying Zhang
- Department of Anesthesiology, Hospital (t.c.m) affiliated to southwest medical university, Luzhou, China
| | - Qing Liu
- Department of Anesthesiology, Hospital (t.c.m) affiliated to southwest medical university, Luzhou, China
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12
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Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss. Int J Mol Sci 2022; 23:ijms23126637. [PMID: 35743082 PMCID: PMC9223703 DOI: 10.3390/ijms23126637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 11/28/2022] Open
Abstract
Evidence indicates that inhalative anesthetics enhance the β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) activity, increase amyloid beta 1-42 (Aβ1–42) aggregation, and modulate dendritic spine dynamics. However, the mechanisms of inhalative anesthetics on hippocampal dendritic spine plasticity and BACE-dependent APP processing remain unclear. In this study, hippocampal slices were incubated with equipotent isoflurane (iso), sevoflurane (sevo), or xenon (Xe) with/without pretreatment of the BACE inhibitor LY2886721 (LY). Thereafter, CA1 dendritic spine density, APP processing-related molecule expressions, nectin-3 levels, and long-term potentiation (LTP) were tested. The nectin-3 downregulation on LTP and dendritic spines were evaluated. Sevo treatment increased hippocampal mouse Aβ1–42 (mAβ1–42), abolished CA1-LTP, and decreased spine density and nectin-3 expressions in the CA1 region. Furthermore, CA1-nectin-3 knockdown blocked LTP and reduced spine density. Iso treatment decreased spine density and attenuated LTP. Although Xe blocked LTP, it did not affect spine density, mAβ1–42, or nectin-3. Finally, antagonizing BACE activity partly restored sevo-induced deficits. Taken together, our study suggests that sevo partly elevates BACE activity and interferes with synaptic remodeling, whereas iso mildly modulates synaptic changes in the CA1 region of the hippocampus. On the other hand, Xe does not alternate dendritic spine remodeling.
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Ma C, Yu X, Li D, Fan Y, Tang Y, Tao Q, Zheng L. Inhibition of SET domain-containing (lysine methyltransferase) 7 alleviates cognitive impairment through suppressing the activation of NOD-like receptor protein 3 inflammasome in isoflurane-induced aged mice. Hum Exp Toxicol 2022; 41:9603271211061497. [PMID: 35187972 DOI: 10.1177/09603271211061497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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.
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Affiliation(s)
- Chao Ma
- Department of Anesthesiology, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xianjun Yu
- Department of Anesthesiology, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Dong Li
- Department of General Surgery, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Youwen Fan
- Department of General Surgery, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Yajun Tang
- Department of General Surgery, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Qiang Tao
- Department of General Surgery, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Lei Zheng
- Department of Anesthesiology, 543160the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
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14
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Cascella M. Anesthetics and translational research. PERIOPERATIVE NEUROSCIENCE 2022:25-40. [DOI: 10.1016/b978-0-323-91003-3.00008-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Anesthesia can alter the levels of corticosterone and the phosphorylation of signaling molecules. BMC Res Notes 2021; 14:363. [PMID: 34538274 PMCID: PMC8451088 DOI: 10.1186/s13104-021-05763-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/27/2021] [Indexed: 11/11/2022] Open
Abstract
Objective Neuroscience research using laboratory animals has increased over the years for a number of reasons. Some of these studies require the use of anesthetics for surgical procedures. However, the use of anesthetics promotes several physiological changes that may interfere with experimental results. Although the anesthetics and methods of delivery used to vary, one of the most common is ketamine associated with another compound such as xylazine. We aimed to evaluate the effect of ketamine and xylazine (KX) on corticosterone levels and on the degree of phosphorylation of p44/42 (ERK1/2), Src kinases and calcium/calmodulin-dependent kinase II (CAMKII). We also compared the effects of KX on sleep deprivation, which is known to affect the hormonal profile including corticosterone. Results We found that the use of KX can increase corticosterone levels and alter the degree of phosphorylation of signaling proteins. Supplementary Information The online version contains supplementary material available at 10.1186/s13104-021-05763-w.
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Ma D, Liu J, Wei C, Shen W, Yang Y, Lin D, Wu A. Activation of CD200-CD200R1 Axis Attenuates Perioperative Neurocognitive Disorder Through Inhibition of Neuroinflammation in Mice. Neurochem Res 2021; 46:3190-3199. [PMID: 34392443 DOI: 10.1007/s11064-021-03422-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 07/24/2021] [Accepted: 08/04/2021] [Indexed: 10/20/2022]
Abstract
Perioperative neurocognitive disorder (PND) is the mild cognitive impairment associated with surgery and anesthesia. It is a common surgical complication in the elderly. An important mechanism of PND is the surgically induced neuroinflammation. The interaction between the neuronal surface protein CD200 and its receptor in microglia, CD200R1, is an important regulatory pathway to control neuroinflammation. However, the potential role of the CD200-CD200R1 pathway in the acute period of PND has not been fully investigated. In this study, in a PND mouse model, we first measured the protein expression level of CD200, CD200R1, and the related pro- and anti-inflammatory cytokines in the hippocampus. Then, we investigated cognitive function, neuroinflammation and postsynaptic density protein 95 (PSD-95) expression after the injection of CD200-Fc (agonist), CD200R1-Fc (antagonist) or IgG1-Fc (vehicle) into lateral ventricle in PND models. Compared with the control group, the expression of CD200 was up-regulated at day 1 after surgery in PND models. The injection of the CD200-Fc into the lateral ventricle could mitigate primed neuroinflammation and cognitive decline, increase the expression of PSD-95 at day 1 after surgery in PND models. In conclusion, we have demonstrated that CD200-CD200R1 signaling was involved in the acute inflammatory process of PND, and activating CD200R1 can inhibit neuroinflammation and attenuate PND. Thus, the CD200-CD200R1 axis is a potential novel target for PND prevention and treatment.
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Affiliation(s)
- Danxu Ma
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Jinhu Liu
- Department of Anesthesiology, Beijing First Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, 100021, People's Republic of China
| | - Changwei Wei
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Wenzhen Shen
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Yinan Yang
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Dandan Lin
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Anshi Wu
- Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, People's Republic of China.
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Relationship between Artificial Intelligence-Based General Anesthetics and Postoperative Cognitive Dysfunction. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:5553029. [PMID: 33868620 PMCID: PMC8032528 DOI: 10.1155/2021/5553029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/08/2021] [Accepted: 03/20/2021] [Indexed: 11/23/2022]
Abstract
Postoperative cognitive dysfunction (POCD) refers to the complications of the central nervous system before and after surgery in patients without mental disorders. Many studies have shown that surgical anesthesia may cause POCD, especially in elderly patients. This article aims to study the relationship between artificial intelligence-based general anesthetics and postoperative cognitive dysfunction. This article first describes and classifies artificial intelligence, introduces its realization method, machine learning algorithms, and briefly introduces the basic principles of regression and classification methods in machine learning; then, the principles and techniques of general anesthetics are proposed. The pathogenesis of postoperative cognitive dysfunction (POCD) is explained in detail. Finally, the effect of anesthetics on postoperative cognitive dysfunction is obtained from both inhaled anesthetics and intravenous anesthetics. The impact on postoperative cognitive function is explained. The experimental results in this article show that there is no statistically significant difference in the two groups of patients' age, gender ratio, body mass index, education level, preoperative comorbidities, and other general indicators. Through the use of EEG bispectral index monitors to monitor the depth of anesthesia and postoperative cognitive dysfunction, first, there was no obvious relationship between the occurrence of postoperative cognitive dysfunction at 1, 5, 10, and 50 days and discharge time. The comprehensive monitoring group can reduce the clinical dose of preventive medication and cis-atracurium and shorten the patient's recovery time, extubation time, and recovery time. In addition, it can also reduce the increase of serum protein S100β in elderly patients and reduce the incidence of early postoperative cognitive dysfunction.
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Lv G, Li C, Wang W, Li N, Wang K. Silencing SP1 Alleviated Sevoflurane-Induced POCD Development via Cholinergic Anti-inflammatory Pathway. Neurochem Res 2020; 45:2082-2090. [PMID: 32594292 DOI: 10.1007/s11064-020-03070-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 06/03/2020] [Accepted: 06/12/2020] [Indexed: 12/26/2022]
Abstract
Postoperative cognitive dysfunction (POCD) is a common complication induced by anesthesia or surgery, which affects the concentration, cognition and memory of patients. Sevoflurane, a clinical anesthetic, could stimulate neuro-inflammation and lead to POCD. Recent studies found that specificity protein 1 (SP1) participates in the development of neurological diseases. Our study aims to elucidate the role of SP1 in sevoflurane-induced POCD pathogenesis. We anesthetized Sprague-Dawley rats and treated the primary hippocampal neurons with sevoflurane to construct the in vivo and in vitro POCD models. Besides, the expression and regulatory mechanism of SP1 in the pathogenesis of POCD were explored. According to the results, sevoflurane anesthesia impaired the cognitive functions of rat, significantly elevated SP1 expression and inactivated the cholinergic anti-inflammatory pathway (CAP) both in vivo and in vitro. Moreover, the sevoflurane-treated rats and neurons also exhibited obvious inflammatory responses and enhanced apoptosis. Loss-of-function assay indicated that SP1 knockdown rescued the deactivation of CAP and alleviated the sevoflurane-induced neuro-inflammation and apoptosis in rat hippocampus. Generally, our study documented that the sevoflurane-induced SP1 up-regulation affected the activation of CAP, leading to the aggravated neuro-inflammation and apoptosis. This may provide a novel sight for POCD therapy.
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Affiliation(s)
- Guoying Lv
- Department of the First Anesthesiology, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Chuangang Li
- Department of the First Anesthesiology, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Weiwei Wang
- Department of the First Anesthesiology, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Ning Li
- Department of the First Anesthesiology, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Kai Wang
- Department of Hepatology, QiLu Hospital of Shandong University, 107 West Wenhua Road, Jinan, 250012, Shandong, China.
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Lei D, Sha Y, Wen S, Xie S, Liu L, Han C. Dexmedetomidine May Reduce IL-6 Level and the Risk of Postoperative Cognitive Dysfunction in Patients After Surgery: A Meta-Analysis. Dose Response 2020; 18:1559325820902345. [PMID: 32076394 PMCID: PMC7003176 DOI: 10.1177/1559325820902345] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 12/11/2019] [Accepted: 12/19/2019] [Indexed: 01/27/2023] Open
Abstract
Dexmedetomidine (DEX) was widely used in clinical work. However, the effectiveness of DEX on postoperative cognitive dysfunction (POCD) was still need to be confirmed. The aim of this meta-analysis was to explore whether DEX can reduce the incidence of POCD on the first day and seventh postoperative day. The results showed that lower incidence of POCD associated with DEX treatment on the first (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.31-0.54) or seventh postoperative day (OR: 0.53; 95% CI: 0.36-0.77). Mini-Mental State Examination scores on the first (mean difference [MD]: 4.67; 95% CI: 1.72-7.63) and seventh postoperative days (MD: 3.71; 95% CI: 2.51-4.90) were higher in DEX use group than that in physiological saline group. Meanwhile, neuron-specific enolase (NSE; MD: −3.99; 95% CI: −6.20 to −1.78) and interleukin 6 (IL-6) levels (MD: −17.53; 95% CI: −21.51 to −13.54) on the first postoperative day in DEX group were lower than that in the physiological saline group. This meta-analysis suggested that DEX use could reduce the risk of POCD and the reduction in levels of NSE and IL-6 can improve long-term cognitive dysfunction and anti-inflammation.
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Affiliation(s)
- Daoyun Lei
- Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Yeqin Sha
- Nanjing Medical University, Jiangsu, China
| | - Shuang Wen
- Nanjing Medical University, Jiangsu, China
| | - Songhui Xie
- Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Li Liu
- Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Chao Han
- Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Yixing Clinical College, Medical College of Yangzhou University, Yixing, Jiangsu, China
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Guida F, Palazzo E, Boccella S, Luongo L, Scala G, Gargano F, Pieretti G, Marabese I, Scafuro M, de Novellis V, Maione S. Pharmacological Considerations for the Use of General Anesthetics in the Elderly. NEUROMETHODS 2020:133-145. [DOI: 10.1007/978-1-4939-9891-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway. Neuromolecular Med 2019; 22:227-238. [DOI: 10.1007/s12017-019-08578-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 10/18/2019] [Indexed: 12/18/2022]
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The mechanism of lipopolysaccharide administration-induced cognitive function impairment caused by glucose metabolism disorder in adult rats. Saudi J Biol Sci 2019; 26:1268-1277. [PMID: 31516357 PMCID: PMC6734155 DOI: 10.1016/j.sjbs.2019.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/26/2019] [Accepted: 06/30/2019] [Indexed: 11/22/2022] Open
Abstract
This essay aims to make investigation on the mechanism of glucose metabolism disorder and Lipopolysaccharide administration-induced cognitive function impairment in adult rats with surgery. Methods: Divide the objects, 40 male Sprague-Dawley rats at the age of 9 months, into 4 groups. Provide unilateral nephrectomy surgery and/or lipopolysaccharide intraperitoneal injection. Postoperative cognitive function evaluation would be tested by the Morris water maze. Rats with Postoperative Cognitive Dysfunction (POCD) were scanned to analyze the brain glucose metabolism by means of 18F-FDG PET/CT. Phosphatidylinositol 3-Kinase (PI3K), Protein Kinase β (AKT), Insulin Substrates Receptor-2 (IRS-2) and Glucose Transporter 4 (GLUT4) were detected as well. Data will be captured through gene expression in POCD rats via Quantitative Real-Time PCR (QRT-PCR). On the other side, Western Blot was used to measure the expression levels of IRS-2, p-IRS-2, p-PI3K, PI3K, p-AKT, AKT, GLUT4, and p-GLUT4. Results: During the Morris water maze test, the staging time (latency) of rats in each group was becoming short gradually as the training progressed. The incubation time of Day 5 of each group was shorter than that of Day 1 (P < 0.05). On the Day 3 after the surgery, the average target quadrant residence time of Group S+L (100 μg/Kg) was shorter, compared with Group C, L and S. Of which, the average number of perforation was reduced greater than that of Group C (P < 0.05). The average swimming speed of the groups is of no distinct difference (P > 0.05). After the operation, there was no great difference shown among the subjects (P > 0.05) in the average residence time of the target quadrant, the mean number of passages, and the mean swimming speed. On Day 3, the average latency of Group S+L (100 μg/Kg) was longer than Group C (P < 0.05) in the working memory test after the operation. The average latency of rats in Group L and S was showed longer than that in Group C, with tiny difference (P > 0.05). In the 7-Day working memory test, the average latency of the rats in Group L, S and S+L (100 μg/Kg) was obviously longer than that in Group C. Comparing to preoperative rats, POCD rats of Group S+L (100 μg/Kg) were scanned by 18F-FDG PET/CT three days later after the operation. Its SUVmax of the frontal and temporal lobe areas were decreased significantly (P < 0.05). However, difference degree was not significantly shown in the SUVmax between Group C and the preoperative rats (P > 0.05). In comparison with the gene expression of of Group C, the PI3K, IRS-2, AKT and GLUT4 mRNA genes are the key genes in the insulin signaling pathways of the hippocampus of the POCD rats. The expression level was reduced. The expression level of all protein of PI3K, IRS-2, GLUT4 and AKT in the POCD rats was of no great contrast with that in Group C. But for IRS-2 protein, the phosphorylation level has increased, and meanwhile decreased for AKT, PI3K and GLUT4 proteins (P < 0.05). Conclusions: Adult SD rats cognitive dysfunction model treated with unilateral nephrectomy combined and 100 μg/kg LPS intraperitoneal injection were led to abnormal both brain glucose metabolism and insulin expression. The proved phenomenal results signal pathway-related proteins PI3K, IRS-2, AKT and GLUT4. It reached the conclusion that surgical trauma, rather than anesthesia, leads to impaired cognitive function. PI3K, IRS-2, AKT, and GLUT4pathway of brain can be partial explanations of the pathogenesis of POCD.
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Key Words
- 18F-FDG PET/CT
- AGE, Advanced Glycation End products
- FDG, Fluorodeoxyglucose
- GLUT4, Glucose Transporter 4
- Glucose metabolism
- IRS-2, Insulin Substrate Receptor-2
- LPS, Lipopolysaccharide
- MAPK, Mitogen-Activated Protein Kinase
- OSEM, Ordered Subsets Expectation Maximization
- PI3K, IRS-2, AKT, and GLUT4 pathway
- PI3K, Phosphatidylinositol 3-Kinase
- POCD, Postoperative Cognitive Dysfunction
- Postoperative cognitive dysfunction
- QRT-PCR, Quantitative Real-Time PCR
- ROS, Reactive Oxygen Species
- SUV, Standard Uptake Value
- Surgical trauma
- TLR4, Toll-like Receptor 4
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Jiang Y, Gao H, Yuan H, Xu H, Tian M, Du G, Xie W. Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues. Neurosci Lett 2019; 709:134372. [DOI: 10.1016/j.neulet.2019.134372] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 06/21/2019] [Accepted: 07/05/2019] [Indexed: 12/22/2022]
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Wang M, Su P, Liu Y, Zhang X, Yan J, An X, Wang X, Gu S. Abnormal expression of circRNA_089763 in the plasma exosomes of patients with post‑operative cognitive dysfunction after coronary artery bypass grafting. Mol Med Rep 2019; 20:2549-2562. [PMID: 31524256 PMCID: PMC6691254 DOI: 10.3892/mmr.2019.10521] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 04/09/2019] [Indexed: 12/24/2022] Open
Abstract
Post-operative cognitive dysfunction (POCD) is a complication of the central nervous system characterized by mental disorders, anxiety, personality changes and impaired memory. POCD occurs frequently after coronary artery bypass grafting (CABG) and can severely affect quality of life for patients. To date, the development of POCD biomarkers remains a challenge. Alterations in the expression of non-coding RNAs from brain tissue and peripheral blood have been linked to POCD. The present study aimed to detect the differential circular RNAs (circRNAs) in plasma exosomes of patients with POCD after CABG. The relative expression levels of circRNAs were analyzed using circRNA microarray analysis in the plasma exosomes of patients with POCD. Differentially altered circRNAs (P<0.05, fold change >1.5) were validated by reverse transcription-quantitative PCR in the plasma exosomes of patients with POCD. The target genes of the microRNAs were predicted using bioinformatics analysis. The functions and signaling pathways of these target genes were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. The microarray results indicated that the levels of nine circRNAs in patients with POCD were higher than those in the control subjects; and six circRNAs were at a lower level than those in control subjects. The RT-qPCR results from patients with POCD showed that only circRNA_089763 of the 15 circRNAs identified was significantly increased compared with control subjects. circRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with POCD. The present study provides evidence for the abnormal expression of POCD-induced circRNA_089763 in human plasma exosomes, as well as the involvement of POCD.
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Affiliation(s)
- Maozhou Wang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Pixiong Su
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Yan Liu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xitao Zhang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Jun Yan
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xiangguang An
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xiaobin Wang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Song Gu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
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Liu PR, Cao F, Zhang Y, Peng S. Electroacupuncture reduces astrocyte number and oxidative stress in aged rats with surgery-induced cognitive dysfunction. J Int Med Res 2019; 47:3860-3873. [PMID: 31311378 PMCID: PMC6726816 DOI: 10.1177/0300060519860026] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Objectives To investigate the effects of electroacupuncture in regulating astrocytes and oxidative stress in a rat model of postoperative cognitive dysfunction (POCD). Methods Male aged Sprague-Dawley rats were randomized to undergo left hepatic lobe resection to induce POCD, followed by either electroacupuncture or no treatment; or similar surgery without left lobe resection or electroacupuncture (sham). Postsurgical cognitive function, hippocampal astrocyte number and oxidative stress indicators were measured. Results At days 1, 3 and 7 following surgery, escape latency was significantly shorter and platform crossing frequency was increased with electroacupuncture versus other groups. At postoperative day 1, the electroacupuncture group showed significantly fewer glial fibrillary acidic protein (GFAP)-positive hippocampal astrocytes versus the POCD model group. In POCD rats, electroacupuncture significantly decreased serum S100 calcium binding protein B and neuron-specific enolase levels, and increased brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels, at days 1, 3 and 7. Electroacupuncture significantly attenuated the hippocampal POCD-induced increase in malondialdehyde and decreased superoxide dismutase levels at day 1 following surgery. Conclusion Electroacupuncture may improve cognitive function in rats with POCD by reducing hippocampal GFAP-positive astrocyte number and suppressing oxidative stress.
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Affiliation(s)
- Pei-Rong Liu
- 1 Department of Anaesthesiology, Seventh People's Hospital of Shanghai University of TCM, Shanghai, China
| | - Feng Cao
- 2 Department of Neurology and Neurological Rehabilitation, Seventh People's Hospital of Shanghai University of TCM, Shanghai, China
| | - Yu Zhang
- 1 Department of Anaesthesiology, Seventh People's Hospital of Shanghai University of TCM, Shanghai, China
| | - Sheng Peng
- 1 Department of Anaesthesiology, Seventh People's Hospital of Shanghai University of TCM, Shanghai, China
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26
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Yan WJ, Wang DB, Ren DQ, Wang LK, Hu ZY, Ma YB, Huang JW, Ding SL. AMPKα1 overexpression improves postoperative cognitive dysfunction in aged rats through AMPK-Sirt1 and autophagy signaling. J Cell Biochem 2019; 120:11633-11641. [PMID: 30775803 DOI: 10.1002/jcb.28443] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 12/01/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023]
Abstract
Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients who undergo surgery involving anesthesia. Its underlying mechanisms remain unclear. Autophagy plays an important role in the damage and repair of the nervous system and is associated with the development of POCD. Using a rat model, adenosine monophosphate-activated protein kinase α1 (AMPKα1), an important autophagy regulator, was found to be significantly downregulated in rats with POCD that was induced by sevoflurane anesthesia or by appendectomy. Overexpression of AMPKα1-ameliorated POCD, as indicated by decreased escape latencies and increased target quadrant swimming times, swimming distances, and platform crossing times during Morris water maze tests. AMPKα1 overexpression activated autophagy signals by increasing the expression of light chain 3 II (LC3-II) and Beclin1 and decreasing the expression of p62 in the hippocampus of rats with POCD. Moreover, blocking autophagy by 3-methyladenine partly attenuated AMPKα1-mediated POCD improvement. Furthermore, overexpression of AMPKα1 could upregulate the expression of p-AMPK and Sirt1 in the hippocampus of rats with POCD. Intriguingly, inhibiting AMPK signals via Compound C effectively attenuated AMPKα1-mediated POCD improvement, concomitant with the downregulation of p-AMPK, Sirt1, LC3-II, and Beclin1 and the upregulation of p62. We thus concluded that overexpression of AMPKα1 can improve POCD via the AMPK-Sirt1 and autophagy signaling pathway.
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Affiliation(s)
- Wen-Jun Yan
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Da-Bin Wang
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Dong-Qing Ren
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Ling-Kai Wang
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Zhong-Yuan Hu
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Ya-Bing Ma
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Jin-Wen Huang
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Shao-Li Ding
- Department of Anesthesiology, Gansu Provincial Hospital, Lanzhou, Gansu, China
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Cascella M, Fiore M, Leone S, Carbone D, Di Napoli R. Current controversies and future perspectives on treatment of intensive care unit delirium in adults. World J Crit Care Med 2019; 8:18-27. [PMID: 31240172 PMCID: PMC6582227 DOI: 10.5492/wjccm.v8.i3.18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/19/2019] [Accepted: 05/05/2019] [Indexed: 02/06/2023] Open
Abstract
Delirium is the most frequent manifestation of acute brain dysfunction in intensive care unit (ICU). Although antipsychotics are widely used to treat this serious complication, recent evidence has emphasized that these agents did not reduce ICU delirium (ICU-D) prevalence and did not improve survival, length of ICU or hospital stay after its occurrence. Of note, no pharmacological strategy to prevent or treat delirium has been identified, so far. In this scenario, new scientific evidences are urgently needed. Investigations on specific ICU-D subgroups, or focused on different clinical settings, and studies on medications other than antipsychotics, such as dexmedetomidine or melatonin, may represent interesting fields of research. In the meantime, because there is some evidence that ICU-D can be effectively prevented, the literature suggests strengthening all the strategies aimed at prevention through no-pharmacological approaches mostly focused on the correction of risk factors. The more appropriate strategy useful to treat established delirium remains the use of antipsychotics managed by choosing the right doses after a careful case-by-case analysis. While the evidence regarding the use of dexmedetomidine is still conflicting and sparse, this drug offers interesting perspectives for both ICU-D prevention and treatment. This paper aims to provide an overview of current pharmacological approaches of evidence-based medicine practice. The state of the art of the on-going clinical research on the topic and perspectives for future research are also addressed.
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Affiliation(s)
- Marco Cascella
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples 80049, Italy
| | - Marco Fiore
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Sebastiano Leone
- Division of Infectious Diseases, “San Giuseppe Moscati” Hospital, Avellino 83100, Italy
| | - Domenico Carbone
- Department of Emergency Medicine, Umberto I Hospital, Nocera Inferiore, Salerno 84014, Italy
| | - Raffaela Di Napoli
- Department of Anesthesiology, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles 1000, Belgium
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Zhao ZF, Du L, Gao T, Bao L, Luo Y, Yin YQ, Wang YA. Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats. Neural Regen Res 2019; 14:1029-1036. [PMID: 30762015 PMCID: PMC6404482 DOI: 10.4103/1673-5374.250621] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The α5 subunit-containing gamma-amino butyric acid type A receptors (α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose (1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young (3-month-old) and aged (24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia. The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China (approval No. NBCDSER-IACUC-2015128) in December 2015.
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Affiliation(s)
- Zi-Fang Zhao
- Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
| | - Lei Du
- Department of Radiology, China-Japan Friendship Hospital, Beijing, China
| | - Teng Gao
- Department of Anesthesiology, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing, China
| | - Lin Bao
- Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
| | - Yuan Luo
- Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China
| | - Yi-Qing Yin
- Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
| | - Yong-An Wang
- Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China
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Abstract
Abstract
Quality has been defined by six domains: effective, equitable, timely, efficient, safe, and patient centered. Quality of anesthesia care can be improved through measurement, either through local measures in quality improvement or through national measures in value-based purchasing programs. Death directly related to anesthesia care has been reduced, but must be measured beyond simple mortality. To improve perioperative care for our patients, we must take shared accountability for all surgical outcomes including complications, which has traditionally been viewed as being surgically related. Anesthesiologists can also impact public health by being engaged in improving cognitive recovery after surgery and addressing the opiate crisis. Going forward, we must focus on what patients want and deserve: improved patient-oriented outcomes and satisfaction with our care. By listening to our patients and being engaged in the entire perioperative process, we can make the greatest impact on perioperative care.
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30
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Zhou Y, Li Y, Wang K. Bispectral Index Monitoring During Anesthesia Promotes Early Postoperative Recovery of Cognitive Function and Reduces Acute Delirium in Elderly Patients with Colon Carcinoma: A Prospective Controlled Study using the Attention Network Test. Med Sci Monit 2018; 24:7785-7793. [PMID: 30378591 PMCID: PMC6354643 DOI: 10.12659/msm.910124] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Bispectral index (BIS) monitoring can reduce the duration of anesthesia. This study aimed to evaluate the effects of BIS monitoring during surgery for resection of colon carcinoma in elderly patients using the Attention Network Test (ANT) to study alerting, orienting, and executive functions, and the Confusion Assessment Method (CAM). Material/Methods Eighty-one patients (65–75 years) underwent radical surgery for colon carcinoma with general intravenous anesthesia, propofol (6–8 mg/kg/h), vecuronium (0.03–0.05 mg/kg/min), and remifentanil (0.1–0.2 μg/kg/min). The BIS group (n=41) underwent adjustment of anesthesia to maintain a BIS value between 40–60; the non-BIS group (N=40) underwent standard intraoperative hemodynamic monitoring. Primary endpoints were alerting, orienting, and executive functions assessed pre-operatively and on postoperative days 1 and 5 using the ANT; the secondary endpoint was delirium during the first five postoperative days, assessed using the CAM. Results Propofol and remifentanil doses were significantly lower in the BIS group compared with the non-BIS group (P<0.001). Alerting, orienting, and executive functions showed no differences between the two groups pre-operatively but were impaired in both groups on postoperative day 1 compared with pre-operative levels (P<0.001). On postoperative day 5, alerting (P=0.607) and orienting (P=0.851) functions recovered in the BIS group but remained impaired in the non-BIS group (P<0.001). Delirium was significantly lower in the BIS group compared with the non-BIS group (17.5% vs. 27.5%) (P<0.001). Conclusions BIS-guided anesthesia was associated with reduced anesthetic exposure, early postoperative recovery of alerting and orienting functions, and reduced postoperative delirium.
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Affiliation(s)
- Yumei Zhou
- Department of Anesthesiology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Yuanhai Li
- Department of Anesthesiology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Kai Wang
- Department of Neurology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China (mainland)
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31
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Zhang WL, Chi YL, Wang LZ, Liu H, Zhao LX, Su F. Administrations of Preoperative Shenmai Injection and Postoperative Shenfu Injection, Two Ginseng Containing TCM Formulas, Improve Cognitive Dysfunction in Aged Rats. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2018; 46:1065-1078. [PMID: 30001643 DOI: 10.1142/s0192415x18500556] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Postoperative cognitive dysfunction (POCD) is one of the major complications in patients who have undergone surgeries. Reduction of surgery-induced inflammation and perioperative stress responses may prevent the development of POCD. As recent experimental data have suggested, Shenmai and Shenfu injections, two ginseng containing formulations, may improve cognition. We designed this study using aged rats as an experimental model to determine the effect of combined perioperative Shenmai injection and Shenfu injection in preventing the development of POCD and exploring the underlying mechanism of this intervention. Aged rats were randomized into one of the two groups. Rats in the experiment group received preoperative Shenmai injection and postoperative Shenfu injection while those of the control group did not receive this treatment. Study results indicate that the memory and cognitive ability of rats in the experiment group were significantly better than those of the control group at postoperative day 1 as well as at day 3. Plasma levels of neuron-specific enolase (NSE), S-100 [Formula: see text] protein, interleukin-6 (IL-6), tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]), cortisol (COR), aldosterone (ALD), and adenocorticotropic hormone (ACTH) were significantly lower in the experiment group than in those of the control group (day 1 postoperatively). The plasma level of NSE on postoperative day 3 remained lower in the experimental group than in those of the control group. Our experimental results indicate that preoperative Shenmai and postoperative Shenfu injections facilitate conscious recovery and prevent postoperative cognitive decline. This anti-POCD effect may be a result of minimizing surgery-induced inflammation and reduction of perioperative stress responses by these injections.
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Affiliation(s)
- Wei-Liang Zhang
- * Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Yong-Liang Chi
- † Department of Anesthesiology, Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Lian-Zhu Wang
- † Department of Anesthesiology, Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Hui Liu
- ‡ Department of General Surgery, Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Lu-Xi Zhao
- † Department of Anesthesiology, Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Fan Su
- † Department of Anesthesiology, Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
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