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Yang Y, Song S, Wang H, Ma Z, Gao Q. The antioxidative effect of STAT3 involved in cellular vulnerability to isoflurane. BMC Neurosci 2024; 25:75. [PMID: 39633283 PMCID: PMC11619428 DOI: 10.1186/s12868-024-00911-x] [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: 07/16/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The vulnerable period to neurotoxicity of isoflurane overlaps with a developmental stage characterized by programmed neuronal death. STAT3 has been identified as a crucial molecule involved in survival pathways during this period. We aimed to investigate the role of STAT3 in cellular vulnerability to isoflurane. METHODS C57/BL6 mice on postnatal day 7 or 21, primary neurons derived from mice embryos at gestational days 14-16 and cultured for 5 or 14 days, as well as human neuroglioma U251 cells were treated with isoflurane. A plasmid containing human wild-type STAT3, STAT3 anti-sense oligonucleotide, STAT3 specific inhibitor STA21, proteasome inhibitor MG-132 and calcineurin inhibitor FK506 were utilized to evaluate the influence of STAT3 levels on isoflurane-induced cytotoxicity. The levels of Western blot results, mRNA, intracellular ROS, apoptotic rate, and calcineurin activity were analyzed using unpaired Student's t-test or one-way ANOVA followed by Bonferroni post hoc test, as appropriate. RESULTS Elevated levels of STAT3, reduced activity of calcineurin, as well as a diminished response to isoflurane-induced calcineurin activation and neuroapoptosis were observed in more mature brain or neurons. Isoflurane accelerated the degradation of ubiquitin-conjugated proteins but did not facilitate ubiquitin conjugation to proteins. STAT3 was of particular importance in the all ubiquitin-conjugated proteins degraded by isoflurane. Knockdown or inhibition of STAT3 nuclear translocation exacerbated isoflurane-induced oxidative injury and apoptosis, while STAT3 overexpression mitigated these effects. Finally, this study demonstrated that FK506 pretreatment mitigated the apoptosis, ROS accumulation, and the impairment of neurite growth in primary neurons after exposed to isoflurane. CONCLUSIONS These findings indicate that specific regulation of STAT3 was closely related with the cellular vulnerability to isoflurane via an antioxidative pathway.
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Affiliation(s)
- Yan Yang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, 210008, China
| | - Shiyu Song
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China
| | - Hongwei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China.
| | - Zhengliang Ma
- Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, 210008, China.
| | - Qian Gao
- Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, 210008, China.
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Barton K, Yellowman RD, Holm T, Beaulieu F, Zuckerberg G, Gwal K, Setty BN, Janitz E, Hwang M. Pre-clinical and clinical trials for anesthesia in neonates: gaps and future directions. Pediatr Radiol 2024; 54:2143-2156. [PMID: 39349661 DOI: 10.1007/s00247-024-06066-5] [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: 02/24/2024] [Revised: 09/17/2024] [Accepted: 09/21/2024] [Indexed: 12/13/2024]
Abstract
Literature examining possible deleterious effects of anesthesia exposure on the developing brain has increased substantially over the past 30 years. Initial concerning findings in animal models, both rodents and non-human primates, prompted increasingly thorough examinations in humans, including randomized controlled trials. This review will provide a concise overview of what we know about anesthesia and the developing brain: the background in animal studies, the most robust results we have in humans, and the work yet to be done. This is particularly relevant to a pediatric radiology audience because we have the unique opportunity to modify anesthesia exposure during imaging through innovation.
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Affiliation(s)
- Katherine Barton
- Department of Radiology, Oregon Health & Science University, Portland, OR, USA.
- Department of Diagnostic Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code L340, Portland, OR, 97239, USA.
| | | | - Tara Holm
- Department of Radiology, University of Minnesota, Masonic Children's Hospital, Minneapolis, MN, USA
| | - Forrest Beaulieu
- Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gabriel Zuckerberg
- Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kriti Gwal
- Department of Radiology, Nemours Children's Hospital, Wilmington, DE, USA
| | - Bindu N Setty
- Department of Radiology, Boston University, Boston, MA, USA
| | - Emily Janitz
- Department of Radiology, Akron Children's Hospital, Akron, OH, USA
| | - Misun Hwang
- Department of Radiology, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Mackiewicz J, Lisek M, Tomczak J, Sakowicz A, Guo F, Boczek T. Perinuclear compartment controls calcineurin/MEF2 signaling for axonal outgrowth of hippocampal neurons. Front Mol Neurosci 2024; 17:1494160. [PMID: 39654556 PMCID: PMC11625814 DOI: 10.3389/fnmol.2024.1494160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/04/2024] [Indexed: 12/12/2024] Open
Abstract
Central to the process of axon elongation is the concept of compartmentalized signaling, which involves the A-kinase anchoring protein (AKAP)-dependent organization of signaling pathways within distinct subcellular domains. This spatial organization is also critical for translating electrical activity into biochemical events. Despite intensive research, the detailed mechanisms by which the spatial separation of signaling pathways governs axonal outgrowth and pathfinding remain unresolved. In this study, we demonstrate that mAKAPα (AKAP6), located in the perinuclear space of primary hippocampal neurons, scaffolds calcineurin, NFAT, and MEF2 transcription factors for activity-dependent axon elongation. By employing anchoring disruptors, we show that the mAKAPα/calcineurin/MEF2 signaling pathway, but not NFAT, drives the process of axonal outgrowth. Furthermore, mAKAPα-controlled axonal elongation is linked to the changes in the expression of genes involved in Ca2+/cAMP signaling. These findings reveal a novel regulatory mechanism of axon growth that could be targeted therapeutically for neuroprotection and regeneration.
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Affiliation(s)
- Joanna Mackiewicz
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Malwina Lisek
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Julia Tomczak
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Feng Guo
- Department of Pharmaceutical Toxicology, China Medical University, Shenyang, China
- Department of Pharmacy, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Tomasz Boczek
- Department of Molecular Neurochemistry, Medical University of Lodz, Lodz, Poland
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Li R, Zhang Y, Zhu Q, Wu Y, Song W. The role of anesthesia in peri‑operative neurocognitive disorders: Molecular mechanisms and preventive strategies. FUNDAMENTAL RESEARCH 2024; 4:797-805. [PMID: 39161414 PMCID: PMC11331737 DOI: 10.1016/j.fmre.2023.02.007] [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: 10/11/2022] [Revised: 12/21/2022] [Accepted: 02/15/2023] [Indexed: 03/18/2023] Open
Abstract
Peri-operative neurocognitive disorders (PNDs) include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Children and the elderly are the two populations most vulnerable to the development of POD and POCD, which results in both high morbidity and mortality. There are many factors, including neuroinflammation and oxidative stress, that are associated with POD and POCD. General anesthesia is a major risk factor of PNDs. However, the molecular mechanisms of PNDs are poorly understood. Dexmedetomidine (DEX) is a useful sedative agent with analgesic properties, which significantly improves POCD in elderly patients. In this review, the current understanding of anesthesia in PNDs and the protective effects of DEX are summarized, and the underlying mechanisms are further discussed.
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Affiliation(s)
- Ran Li
- The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou 325035, China
| | - Yun Zhang
- The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Qinxin Zhu
- The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou 325035, China
| | - Yili Wu
- The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China
| | - Weihong Song
- The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou 325035, China
- The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China
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Ge Y, Ming L, Xu D. Sevoflurane-induced cognitive effect on α7-nicotine receptor and M 1 acetylcholine receptor expression in the hippocampus of aged rats. Neurol Res 2024; 46:593-604. [PMID: 38747300 DOI: 10.1080/01616412.2024.2338031] [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: 02/07/2024] [Accepted: 03/28/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Sevoflurane treatment increases the incidence of postoperative cognitive dysfunction (POCD), and patients with POCD show a decline in cognitive abilities compared to preoperative levels. OBJECTIVES This study aimed to investigate whether the activation of α7 nicotinic acetylcholine receptor (α7nAChR) and the expression of M1 acetylcholine receptor (mAChR M1) in the hippocampus affects the cognitive function of aged rats. METHODS Forty-eight Sprague-Dawley (SD) rats of 1-week- and 12-months-old were divided into eight groups: four groups for α7nAChR and four groups for mAChR M1, respectively. All SD rats received 1.0-02% sevoflurane for α7nAChR and 1.0-02% sevoflurane for mAChR M1 for 2-6 h, respectively. The Y-maze test was used to assess the ability to learn and memory after receiving sevoflurane for 7 days at the same moment portion. RT-PCR was used to determine the expression of α7nAChR and mAChR M1 in the hippocampus of rats. RESULTS The α7nAChR mitigated the formation of sevoflurane-induced memory impairment by modulating the translocation of NR2B from the intracellular reservoir to the cell surface reservoir within the hippocampus. Next, sevoflurane-induced decline of cognitive function and significantly decreased mAChR M1 expression at mRNA levels. CONCLUSION α7nAChR regulates the trafficking of NR2B in the hippocampus of rats via the Src-family tyrosine kinase (SFK) pathway. This regulation is associated with cognitive deficits induced by sevoflurane in hippocampal development. Sevoflurane affects the cognitive function of rats by suppressing the mAChR M1 expression at mRNA levels in the hippocampus.
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Affiliation(s)
- Yuan Ge
- Department of Anesthesiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Lei Ming
- Department of Radiology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Dedong Xu
- Department of Anesthesiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
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Yang Y, Liu T, Li J, Yan D, Hu Y, Wu P, Fang F, McQuillan PM, Hang W, Leng J, Hu Z. General anesthetic agents induce neurotoxicity through astrocytes. Neural Regen Res 2024; 19:1299-1307. [PMID: 37905879 PMCID: PMC11467951 DOI: 10.4103/1673-5374.385857] [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: 04/19/2023] [Revised: 08/10/2023] [Accepted: 09/09/2023] [Indexed: 11/02/2023] Open
Abstract
ABSTRACT Neuroscientists have recognized the importance of astrocytes in regulating neurological function and their influence on the release of glial transmitters. Few studies, however, have focused on the effects of general anesthetic agents on neuroglia or astrocytes. Astrocytes can also be an important target of general anesthetic agents as they exert not only sedative, analgesic, and amnesic effects but also mediate general anesthetic-induced neurotoxicity and postoperative cognitive dysfunction. Here, we analyzed recent advances in understanding the mechanism of general anesthetic agents on astrocytes, and found that exposure to general anesthetic agents will destroy the morphology and proliferation of astrocytes, in addition to acting on the receptors on their surface, which not only affect Ca2+ signaling, inhibit the release of brain-derived neurotrophic factor and lactate from astrocytes, but are even involved in the regulation of the pro- and anti-inflammatory processes of astrocytes. These would obviously affect the communication between astrocytes as well as between astrocytes and neighboring neurons, other neuroglia, and vascular cells. In this review, we summarize how general anesthetic agents act on neurons via astrocytes, and explore potential mechanisms of action of general anesthetic agents on the nervous system. We hope that this review will provide a new direction for mitigating the neurotoxicity of general anesthetic agents.
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Affiliation(s)
- Yanchang Yang
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Tiantian Liu
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Department of Anesthesiology, Ningbo Women and Children’s Hospital, Ningbo, Zhejiang Province, China
| | - Jun Li
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Department of Anesthesiology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang Province, China
| | - Dandan Yan
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yuhan Hu
- Cell Biology Department, Yale University, New Haven, CT, USA
| | - Pin Wu
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Fuquan Fang
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Patrick M. McQuillan
- Department of Anesthesiology, Penn State Hershey Medical Centre, Penn State College of Medicine, Hershey, PA, USA
| | - Wenxin Hang
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jianhang Leng
- Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Zhiyong Hu
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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Liu JR, Han XH, Yuki K, Soriano SG. Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction. Front Mol Neurosci 2024; 17:1342233. [PMID: 38840775 PMCID: PMC11150584 DOI: 10.3389/fnmol.2024.1342233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 05/02/2024] [Indexed: 06/07/2024] Open
Abstract
Introduction Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3β (GSK-3β). Since ketamine activates GSK-3β, we examined the impact of ketamine on DISC1 and GSK-3β expression. Methods Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3β antagonist, lithium. Cleaved-caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium. Results Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3β and axonal length. Conclusion These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.
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Affiliation(s)
- Jia-Ren Liu
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao Hui Han
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States
| | - Koichi Yuki
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States
- Department of Anaesthesia, Harvard Medical School, Boston, MA, United States
| | - Sulpicio G. Soriano
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States
- Department of Anaesthesia, Harvard Medical School, Boston, MA, United States
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Guan S, Li Y, Xin Y, Wang D, Lu P, Han F, Xu H. Deciphering the dual role of N-methyl-D-Aspartate receptor in postoperative cognitive dysfunction: A comprehensive review. Eur J Pharmacol 2024; 971:176520. [PMID: 38527701 DOI: 10.1016/j.ejphar.2024.176520] [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: 12/04/2023] [Revised: 03/03/2024] [Accepted: 03/20/2024] [Indexed: 03/27/2024]
Abstract
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, adversely impacting patients' recovery, increasing the risk of negative outcomes, prolonged hospitalization, and higher mortality rates. The N-methyl-D-aspartate (NMDA) receptor, crucial for learning, memory, and synaptic plasticity, plays a significant role in the development of POCD. Various perioperative factors, including age and anesthetic use, can reduce NMDA receptor function, while surgical stress, inflammation, and pain may lead to its excessive activation. This review consolidates preclinical and clinical research to explore the intricate relationship between perioperative factors affecting NMDA receptor functionality and the onset of POCD. It discusses the influence of aging, anesthetic administration, perioperative injury, pain, and inflammation on the NMDA receptor-related pathophysiology of POCD. The comprehensive analysis presented aims to identify effective treatment targets for POCD, contributing to the improvement of patient outcomes post-surgery.
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Affiliation(s)
- Shaodi Guan
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yali Li
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yueyang Xin
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Danning Wang
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Pei Lu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fanglong Han
- Department of Anesthesiology, Xiangyang Maternal and Child Health Hospital, Xiangyang, 441003, China
| | - Hui Xu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Shao Y, Zhou Z, Su W. Effects of isoflurane on rats with cerebral ischemia/reperfusion injury and its potential molecular mechanism. Minerva Med 2024; 115:256-257. [PMID: 34269553 DOI: 10.23736/s0026-4806.21.07602-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Yuanyuan Shao
- Department of Anesthesiology, The Second People's Hospital of Nantong, Nantong, China
| | - Zhijun Zhou
- Department of Anesthesiology, The Second People's Hospital of Nantong, Nantong, China
| | - Wei Su
- Department of Anesthesiology, Shannxi Provincial Cancer Hospital, Xi'an, China -
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Liu Z, Pan X, Guo J, Li L, Tang Y, Wu G, Li M, Wang H. Long-term sevoflurane exposure resulted in temporary rather than lasting cognitive impairment in Drosophila. Behav Brain Res 2023; 442:114327. [PMID: 36738841 DOI: 10.1016/j.bbr.2023.114327] [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: 11/28/2022] [Revised: 01/19/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Sevoflurane is the primary inhaled anesthetic used in pediatric surgery. It has been the focus of research since animal models studies found that it was neurotoxic to the developing brain two decades ago. However, whether pediatric general anesthesia can lead to permanent cognitive deficits remained a subject of heated debate. Therefore, our study aims to determine the lifetime neurotoxicity of early long-time sevoflurane exposure using a short-life-cycle animal model, Drosophila melanogaster. To investigate this question, we measured the lifetime changes of two-day-old flies' learning and memory abilities after anesthesia with 3 % sevoflurane for 6 h by the T-maze memory assay. We evaluated the apoptosis, levels of ATP and ROS, and related genes in the fly head. Our results suggest that 6 h 3 % sevoflurane exposure at a young age can only induce transient neuroapoptosis and cognitive deficits around the first week after anesthesia. But this brain damage recedes with time and vanishes in late life. We also found that the mRNA level of caspases and Bcl-2, ROS level, and ATP level increased during this temporary neuroapoptosis process. And mRNA levels of antioxidants, such as SOD2 and CAT, increased and decreased simultaneously with the rise and fall of the ROS level, indicating a possible contribution to the recovery from the sevoflurane impairment. In conclusion, our results suggest that one early prolonged sevoflurane-based general anesthesia can induce neuroapoptosis and learning and memory deficit transiently but not permanently in Drosophila.
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Affiliation(s)
- Ziming Liu
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China
| | - Xuanyi Pan
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China
| | - Jiguang Guo
- School of Basic Medical Sciences, Hebei University, Baoding 071000, Hebei, China
| | - Liping Li
- Institute of Materia Medical, Hebei Centers for Disease Control and Prevention, Shijiazhuang 050021, Hebei, China
| | - Yuxin Tang
- School of Basic Medical Sciences, Hebei University, Baoding 071000, Hebei, China
| | - Guangyi Wu
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China
| | - Ming Li
- School of Basic Medical Sciences, Hebei University, Baoding 071000, Hebei, China.
| | - Hongjie Wang
- Department of Anesthesiology, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China; Hebei Provincial Key Laboratory of Skeletal Metabolic Physiology of Chronic Kidney Disease, Affiliated Hospital of Hebei University, Baoding 071000, Hebei, China.
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11
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Li W, Yi Q, Shi H. Hippocampal gene expression patterns in Sevoflurane anesthesia associated neurocognitive disorders: A bioinformatic analysis. Front Neurol 2022; 13:1084874. [PMID: 36561300 PMCID: PMC9763458 DOI: 10.3389/fneur.2022.1084874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background Several studies indicate general anesthetics can produce lasting effects on cognitive function. The commonly utilized anesthetic agent Sevoflurane has been implicated in neurodegenerative processes. The present study aimed to identify molecular underpinnings of Sevoflurane anesthesia linked neurocognitive changes by leveraging publically available datasets for bioinformatics analysis. Methods A Sevoflurane anesthesia related gene expression dataset was obtained. Sevoflurane related genes were obtained from the CTD database. Neurocognitive disorders (NCD) related genes were downloaded from DisGeNET and CTD. Intersecting differentially expressed genes between Sevoflurane and NCD were identified as cross-talk genes. A protein-protein interaction (PPI) network was constructed. Hub genes were selected using LASSO regression. Single sample gene set enrichment analysis; functional network analysis, pathway correlations, composite network analysis and drug sensitivity analysis were performed. Results Fourteen intersecting cross-talk genes potentially were identified. These were mainly involved in biological processes including peptidyl-serine phosphorylation, cellular response to starvation, and response to gamma radiation, regulation of p53 signaling pathway, AGE-RAGE signaling pathway and FoxO signaling. Egr1 showed a central role in the PPI network. Cdkn1a, Egr1, Gadd45a, Slc2a1, and Slc3a2 were identified as important or hub cross-talk genes. Among the interacting pathways, Interleukin-10 signaling and NF-kappa B signaling enriched among Sevoflurane-related DEGs were highly correlated with HIF-1 signaling enriched in NCD-related genes. Composite network analysis showed Egr1 interacted with AGE-RAGE signaling and Apelin signaling pathways, Cdkn1a, and Gadd45a. Cdkn1a was implicated in in FoxO signaling, PI3K-Akt signaling, ErbB signaling, and Oxytocin signaling pathways, and Gadd45a. Gadd45a was involved in NF-kappa B signaling and FoxO signaling pathways. Drug sensitivity analysis showed Egr1 was highly sensitive to GENIPIN. Conclusion A suite of bioinformatics analysis revealed several key candidate hippocampal genes and associated functional signaling pathways that could underlie Sevoflurane associated neurodegenerative processes.
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Affiliation(s)
- Weiwei Li
- Department of Anesthesiology, The Second Affiliated Hospital of the Shandong First Medical University, Taian, China
| | - Qijun Yi
- Department of Oncology, The Second Affiliated Hospital of the Shandong First Medical University, Taian, China
| | - Huijian Shi
- Department of Anesthesiology, The Second Affiliated Hospital of the Shandong First Medical University, Taian, China,*Correspondence: Huijian Shi
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Ji D, Karlik J. Neurotoxic Impact of Individual Anesthetic Agents on the Developing Brain. CHILDREN (BASEL, SWITZERLAND) 2022; 9:1779. [PMID: 36421228 PMCID: PMC9689007 DOI: 10.3390/children9111779] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/12/2022] [Accepted: 11/14/2022] [Indexed: 08/04/2023]
Abstract
Concerns about the safety of anesthetic agents in children arose after animal studies revealed disruptions in neurodevelopment after exposure to commonly used anesthetic drugs. These animal studies revealed that volatile inhalational agents, propofol, ketamine, and thiopental may have detrimental effects on neurodevelopment and cognitive function, but dexmedetomidine and xenon have been shown to have neuroprotective properties. The neurocognitive effects of benzodiazepines have not been extensively studied, so their effects on neurodevelopment are undetermined. However, experimental animal models may not truly represent the pathophysiological processes in children. Multiple landmark studies, including the MASK, PANDA, and GAS studies have provided reassurance that brief exposure to anesthesia is not associated with adverse neurocognitive outcomes in infants and children, regardless of the type of anesthetic agent used.
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Agarwal S, Schaefer ML, Krall C, Johns RA. Isoflurane Disrupts Postsynaptic Density-95 Protein Interactions Causing Neuronal Synapse Loss and Cognitive Impairment in Juvenile Mice via Canonical NO-mediated Protein Kinase-G Signaling. Anesthesiology 2022; 137:212-231. [PMID: 35504002 PMCID: PMC9332139 DOI: 10.1097/aln.0000000000004264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Inhalational anesthetics are known to disrupt PDZ2 domain-mediated protein-protein interactions of the postsynaptic density (PSD)-95 protein. The aim of this study is to investigate the underlying mechanisms in response to early isoflurane exposure on synaptic PSD-95 PDZ2 domain disruption that altered spine densities and cognitive function. The authors hypothesized that activation of protein kinase-G by the components of nitric oxide (NO) signaling pathway constitutes a mechanism that prevents loss of early dendritic spines and synapse in neurons and cognitive impairment in mice in response to disruption of PDZ2 domain of the PSD-95 protein. METHODS Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 wild-type PDZ2 peptide or soluble guanylyl cyclase activator YC-1 along with their respective controls. Primary neurons at 7 days in vitro were exposed to isoflurane or PSD-95 wild-type PDZ2 peptide for 4 h. Coimmunoprecipitation, spine density, synapses, cyclic guanosine monophosphate-dependent protein kinase activity, and novel object recognition memory were assessed. RESULTS Exposure of isoflurane or PSD-95 wild-type PDZ2 peptide relative to controls causes the following. First, there is a decrease in PSD-95 coimmunoprecipitate relative to N-methyl-d-aspartate receptor subunits NR2A and NR2B precipitate (mean ± SD [in percentage of control]: isoflurane, 54.73 ± 16.52, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 51.32 ± 12.93, P = 0.001). Second, there is a loss in spine density (mean ± SD [spine density per 10 µm]: control, 5.28 ± 0.56 vs. isoflurane, 2.23 ± 0.67, P < 0.0001; and PSD-95 mutant PDZ2 peptide, 4.74 ± 0.94 vs. PSD-95 wild-type PDZ2 peptide, 1.47 ± 0.87, P < 0.001) and a decrease in synaptic puncta (mean ± SD [in percentage of control]: isoflurane, 41.1 ± 14.38, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 50.49 ± 14.31, P < 0.001). NO donor or cyclic guanosine monophosphate analog prevents the spines and synapse loss and decline in the cyclic guanosine monophosphate-dependent protein kinase activity, but this prevention was blocked by soluble guanylyl cyclase or protein kinase-G inhibitors in primary neurons. Third, there were deficits in object recognition at 5 weeks (mean ± SD [recognition index]: male, control, 64.08 ± 10.57 vs. isoflurane, 48.49 ± 13.41, P = 0.001, n = 60; and female, control, 67.13 ± 11.17 vs. isoflurane, 53.76 ± 6.64, P = 0.003, n = 58). Isoflurane-induced impairment in recognition memory was preventable by the introduction of YC-1. CONCLUSIONS Activation of soluble guanylyl cyclase or protein kinase-G prevents isoflurane or PSD-95 wild-type PDZ2 peptide-induced loss of dendritic spines and synapse. Prevention of recognition memory with YC-1, a NO-independent activator of guanylyl cyclase, supports a role for the soluble guanylyl cyclase mediated protein kinase-G signaling in countering the effects of isoflurane-induced cognitive impairment. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Swati Agarwal
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Michele L Schaefer
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Caroline Krall
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Roger A Johns
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
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Williams RA, Johnson KW, Lee FS, Hemmings HC, Platholi J. A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures. Front Mol Neurosci 2022; 15:927149. [PMID: 35813074 PMCID: PMC9260310 DOI: 10.3389/fnmol.2022.927149] [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: 04/23/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function.
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Affiliation(s)
- Riley A. Williams
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States
| | - Kenneth W. Johnson
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States
| | - Francis S. Lee
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States,Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, United States,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
| | - Hugh C. Hemmings
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States,Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States
| | - Jimcy Platholi
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States,*Correspondence: Jimcy Platholi,
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15
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Yang Y, Liu Y, Zhu J, Song S, Huang Y, Zhang W, Sun Y, Hao J, Yang X, Gao Q, Ma Z, Zhang J, Gu X. Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction. Free Radic Biol Med 2022; 178:134-146. [PMID: 34875338 DOI: 10.1016/j.freeradbiomed.2021.12.004] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/20/2021] [Accepted: 12/02/2021] [Indexed: 12/22/2022]
Abstract
Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.
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Affiliation(s)
- Yan Yang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Yue Liu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Jixiang Zhu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Shiyu Song
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China
| | - Yulin Huang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Wei Zhang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Yu'e Sun
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Jing Hao
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Xuli Yang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China
| | - Qian Gao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210093, China
| | - Zhengliang Ma
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
| | - Juan Zhang
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
| | - Xiaoping Gu
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
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16
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Jung S, Kayser EB, Johnson SC, Li L, Worstman HM, Sun GX, Sedensky MM, Morgan PG. Tetraethylammonium chloride reduces anaesthetic-induced neurotoxicity in Caenorhabditis elegans and mice. Br J Anaesth 2022; 128:77-88. [PMID: 34857359 PMCID: PMC8787783 DOI: 10.1016/j.bja.2021.09.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/30/2021] [Accepted: 09/15/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND If anaesthetics cause permanent cognitive deficits in some children, the implications are enormous, but the molecular causes of anaesthetic-induced neurotoxicity, and consequently possible therapies, are still debated. Anaesthetic exposure early in development can be neurotoxic in the invertebrate Caenorhabditis elegans causing endoplasmic reticulum (ER) stress and defects in chemotaxis during adulthood. We screened this model organism for compounds that alleviated neurotoxicity, and then tested these candidates for efficacy in mice. METHODS We screened compounds for alleviation of ER stress induction by isoflurane in C. elegans assayed by induction of a green fluorescent protein (GFP) reporter. Drugs that inhibited ER stress were screened for reduction of the anaesthetic-induced chemotaxis defect. Compounds that alleviated both aspects of neurotoxicity were then blindly tested for the ability to inhibit induction of caspase-3 by isoflurane in P7 mice. RESULTS Isoflurane increased ER stress indicated by increased GFP reporter fluorescence (240% increase, P<0.001). Nine compounds reduced induction of ER stress by isoflurane by 90-95% (P<0.001 in all cases). Of these compounds, tetraethylammonium chloride and trehalose also alleviated the isoflurane-induced defect in chemotaxis (trehalose by 44%, P=0.001; tetraethylammonium chloride by 23%, P<0.001). In mouse brain, tetraethylammonium chloride reduced isoflurane-induced caspase staining in the anterior cortical (-54%, P=0.007) and hippocampal regions (-46%, P=0.002). DISCUSSION Tetraethylammonium chloride alleviated isoflurane-induced neurotoxicity in two widely divergent species, raising the likelihood that it may have therapeutic value. In C. elegans, ER stress predicts isoflurane-induced neurotoxicity, but is not its cause.
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Affiliation(s)
- Sangwook Jung
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Ernst-Bernhard Kayser
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Simon C Johnson
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA; Department of Anesthesiology and Pain Medicine, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, WA, USA
| | - Li Li
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA; Department of Anesthesiology and Pain Medicine, Seattle, WA, USA
| | - Hailey M Worstman
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Grace X Sun
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Margaret M Sedensky
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA; Department of Anesthesiology and Pain Medicine, Seattle, WA, USA
| | - Philip G Morgan
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA; Department of Anesthesiology and Pain Medicine, Seattle, WA, USA.
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17
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Jevtovic-Todorovic V. Sex hormones and the young brain: are we ready to embrace neuroprotective strategies? Br J Anaesth 2021; 128:229-231. [PMID: 34857358 DOI: 10.1016/j.bja.2021.10.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/28/2021] [Indexed: 01/01/2023] Open
Abstract
Growing animal and clinical data continue to point to general anaesthetics as being potentially detrimental to the very young brain. While we are trying to understand the mechanisms responsible for this worrisome phenomenon, we must consider the value of protective strategies that would enable use of currently available general anaesthetics while avoiding histopathological changes and long-lasting impairment in behavioural and cognitive development. Wali and colleagues1 report that the gestational hormone progesterone is a promising 'safening' agent that ameliorates systemic inflammation caused by sevoflurane, a commonly used inhaled anaesthetic, while preventing development of cognitive impairment and an anxious phenotype.
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18
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Hofmann C, Sander A, Wang XX, Buerge M, Jungwirth B, Borgstedt L, Kreuzer M, Kopp C, Schorpp K, Hadian K, Wotjak CT, Ebert T, Ruitenberg M, Parsons CG, Rammes G. Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level. J Alzheimers Dis 2021; 84:1193-1218. [PMID: 34657881 DOI: 10.3233/jad-201185] [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: 11/15/2022]
Abstract
BACKGROUND Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE In the present study, we want to detail the interactions of inhalational anesthetics with Aβ-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aβ oligomerization and Aβ-mediated neurotoxicity on processes related to cognition. METHODS Oligomerization of Aβ 1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aβ 1-42, Aβ 1-40, pyroglutamate-modified amyloid-(AβpE3), and nitrated Aβ (3NTyrAβ), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aβ plaque burden in transgenic AD mice (ArcAβ) after anesthesia. RESULTS Whereas isoflurane and sevoflurane did not affect Aβ 1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AβpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aβ 1-42-induced spine density attenuation. In the presence of Aβ 1-40 and AβpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aβ 1-42 or 3NTyrAβ, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAβ mice. CONCLUSION None of the anesthetics aggravated Aβ-derived AD pathology in vivo. However, Aβ and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aβ 1-42 aggregation, LTP, and spine density.
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Affiliation(s)
- Carolin Hofmann
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Annika Sander
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Xing Xing Wang
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Martina Buerge
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Bettina Jungwirth
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Department of Anesthesiology, University Hospital Ulm, Ulm, Germany
| | - Laura Borgstedt
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Matthias Kreuzer
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Claudia Kopp
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Kenji Schorpp
- Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Kamyar Hadian
- Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Carsten T Wotjak
- Max Planck Institute of Psychiatry, Neuronal Plasticity, Munich, Germany.,Central Nervous System Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Tim Ebert
- Max Planck Institute of Psychiatry, Neuronal Plasticity, Munich, Germany
| | | | | | - Gerhard Rammes
- Department of Anesthesiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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19
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Platholi J, Hemmings HC. Effects of general anesthetics on synaptic transmission and plasticity. Curr Neuropharmacol 2021; 20:27-54. [PMID: 34344292 PMCID: PMC9199550 DOI: 10.2174/1570159x19666210803105232] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 11/22/2022] Open
Abstract
General anesthetics depress excitatory and/or enhance inhibitory synaptic transmission principally by modulating the function of glutamatergic or GABAergic synapses, respectively, with relative anesthetic agent-specific mechanisms. Synaptic signaling proteins, including ligand- and voltage-gated ion channels, are targeted by general anesthetics to modulate various synaptic mechanisms, including presynaptic neurotransmitter release, postsynaptic receptor signaling, and dendritic spine dynamics to produce their characteristic acute neurophysiological effects. As synaptic structure and plasticity mediate higher-order functions such as learning and memory, long-term synaptic dysfunction following anesthesia may lead to undesirable neurocognitive consequences depending on the specific anesthetic agent and the vulnerability of the population. Here we review the cellular and molecular mechanisms of transient and persistent general anesthetic alterations of synaptic transmission and plasticity.
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Affiliation(s)
- Jimcy Platholi
- Cornell University Joan and Sanford I Weill Medical College Ringgold standard institution - Anesthesiology New York, New York. United States
| | - Hugh C Hemmings
- Cornell University Joan and Sanford I Weill Medical College Ringgold standard institution - Anesthesiology New York, New York. United States
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In vivo functions of p75 NTR: challenges and opportunities for an emerging therapeutic target. Trends Pharmacol Sci 2021; 42:772-788. [PMID: 34334250 DOI: 10.1016/j.tips.2021.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/31/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022]
Abstract
The p75 neurotrophin receptor (p75NTR) functions at the molecular nexus of cell death, survival, and differentiation. In addition to its contribution to neurodegenerative diseases and nervous system injuries, recent studies have revealed unanticipated roles of p75NTR in liver repair, fibrinolysis, lung fibrosis, muscle regeneration, and metabolism. Linking these various p75NTR functions more precisely to specific mechanisms marks p75NTR as an emerging candidate for therapeutic intervention in a wide range of disorders. Indeed, small molecule inhibitors of p75NTR binding to neurotrophins have shown efficacy in models of Alzheimer's disease (AD) and neurodegeneration. Here, we outline recent advances in understanding p75NTR pleiotropic functions in vivo, and propose an integrated view of p75NTR and its challenges and opportunities as a pharmacological target.
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21
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Zhu Y, Zhou H, Chen D, Zhou D, Zhao N, Xiong L, Deng I, Zhou X, Zhu Z. New progress of isoflurane, sevoflurane and propofol in hypoxic-ischemic brain injury and related molecular mechanisms based on p75 neurotrophic factor receptor. IBRAIN 2021; 7:132-140. [PMID: 37786902 PMCID: PMC10528789 DOI: 10.1002/j.2769-2795.2021.tb00075.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/17/2021] [Accepted: 06/10/2021] [Indexed: 10/04/2023]
Abstract
Hypoxic ischemic brain injury (HIBI) is one of the most common clinical disorders, especially in neonates. The complex pathophysiology of HIBI is an important cause of disability and even death of patients, however, being without effective clinical treatments. Common anesthetics (such as isoflurane, propofol and sevoflurane) have an adverse impact on neuronal cells for HIBI via the regulation of p75 neurotrophic factor receptor (P75NTR). In order to protect the injured brains and study the effect of underlying treatments, it is particularly significant to understand and master the developmental mechanism of anesthetics for the occurrence of HIBI related molecular mechanisms. Therefore, this paper will mainly review the corresponding pathogenic and protective mechanisms about HIBI binding to the research progress of the role of P75NTR. In conclusion, the effects of neuroprotection and injured nerves are involved in the expression and activation of P75NTR, mainly increased P75NTR mRNA, protein levels and calpain-dependent for propofol, and inducing neuronal apoptosis for isoflurane and sevoflurane, and we look forward to that connection with P75NTR, common anaesthetic and HIBI may be a new direction of research and gain perfect outcomes in the future.
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Affiliation(s)
- Yi Zhu
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Hong‐Su Zhou
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Dong‐Qin Chen
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Di Zhou
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Nan Zhao
- Department of AnesthesiaHospital of Stomatology, Zunyi Medical UniversityZunyiGuizhouChina
| | - Liu‐Lin Xiong
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Issac Deng
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Xin‐Fu Zhou
- Clinical and Health Sciences, University of South AustraliaAdelaide5000South AustraliaAustralia
| | - Zhao‐Qiong Zhu
- School of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
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22
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Dendritic spine remodeling and plasticity under general anesthesia. Brain Struct Funct 2021; 226:2001-2017. [PMID: 34061250 PMCID: PMC8166894 DOI: 10.1007/s00429-021-02308-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/22/2021] [Indexed: 11/29/2022]
Abstract
Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.
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23
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Xu MS, Yin LM, Cheng AF, Zhang YJ, Zhang D, Tao MM, Deng YY, Ge LB, Shan CL. Cerebral Ischemia-Reperfusion Is Associated With Upregulation of Cofilin-1 in the Motor Cortex. Front Cell Dev Biol 2021; 9:634347. [PMID: 33777942 PMCID: PMC7991082 DOI: 10.3389/fcell.2021.634347] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Cerebral ischemia is one of the leading causes of death. Reperfusion is a critical stage after thrombolysis or thrombectomy, accompanied by oxidative stress, excitotoxicity, neuroinflammation, and defects in synapse structure. The process is closely related to the dephosphorylation of actin-binding proteins (e.g., cofilin-1) by specific phosphatases. Although studies of the molecular mechanisms of the actin cytoskeleton have been ongoing for decades, limited studies have directly investigated reperfusion-induced reorganization of actin-binding protein, and little is known about the gene expression of actin-binding proteins. The exact mechanism is still uncertain. The motor cortex is very important to save nerve function; therefore, we chose the penumbra to study the relationship between cerebral ischemia-reperfusion and actin-binding protein. After transient middle cerebral artery occlusion (MCAO) and reperfusion, we confirmed reperfusion and motor function deficit by cerebral blood flow and gait analysis. PCR was used to screen the high expression mRNAs in penumbra of the motor cortex. The high expression of cofilin in this region was confirmed by immunohistochemistry (IHC) and Western blot (WB). The change in cofilin-1 expression appears at the same time as gait imbalance, especially maximum variation and left front swing. It is suggested that cofilin-1 may partially affect motor cortex function. This result provides a potential mechanism for understanding cerebral ischemia-reperfusion.
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Affiliation(s)
- Ming-Shu Xu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei-Miao Yin
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ai-Fang Cheng
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying-Jie Zhang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Di Zhang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Miao-Miao Tao
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yun-Yi Deng
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin-Bao Ge
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chun-Lei Shan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Hogarth K, Vanama RB, Stratmann G, Maynes JT. Singular and short-term anesthesia exposure in the developing brain induces persistent neuronal changes consistent with chronic neurodegenerative disease. Sci Rep 2021; 11:5673. [PMID: 33707598 PMCID: PMC7952562 DOI: 10.1038/s41598-021-85125-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 02/25/2021] [Indexed: 01/31/2023] Open
Abstract
The potential adverse impact of inhalational anesthetics on the developing brain was highlighted by the addition of a medication warning by the U.S. Food and Drug Administration for their use in the pediatric population. To investigate mechanisms by which early life anesthesia exposure could induce long-term neuronal dysfunction, we exposed rats to 1 minimum alveolar concentration sevoflurane at 7 days of life. The animals were raised normally until adulthood (P300) prior to sacrifice and analysis of cortical tissue structure (TEM), mitochondrial quality control and biogenesis pathways (Western blot, ELISA, ADP/ATP content), and markers of oxidative stress, proteotoxicity and inflammation (Western blot, ELISA). We found that early life anesthesia exposure led to adverse changes in mitochondrial quality maintenance pathways, autophagy and mitochondrial biogenesis. Although there was an escalation of oxidative stress markers and an increase in the nuclear localization of stress-related transcription factors, cellular redox compensatory responses were blunted, and oxidative phosphorylation was reduced. We found upregulation of mitochondrial stress and proteotoxicity markers, but a significant reduction of mitochondrial unfolded protein response end-effectors, contributing to an increase in inflammation. Contrary to acute exposure, we did not find an increase in apoptosis. Our findings suggest that a limited, early exposure to anesthesia may produce lasting cellular dysfunction through the induction of a sustained energy deficient state, resulting in persistent neuroinflammation and altered proteostasis/toxicity, mimicking aspects of chronic neurodegenerative diseases.
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Affiliation(s)
- Kaley Hogarth
- Division of Molecular Medicine, SickKids Research Institute, Toronto, Canada
- Department of Anesthesia and Pain Medicine, Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada
| | - Ramesh Babu Vanama
- Division of Molecular Medicine, SickKids Research Institute, Toronto, Canada
- Department of Anesthesia and Pain Medicine, Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada
| | - Greg Stratmann
- Department of Anesthesia and Perioperative Medicine, University of California, San Francisco, San Francisco, USA
| | - Jason T Maynes
- Division of Molecular Medicine, SickKids Research Institute, Toronto, Canada.
- Department of Anesthesia and Pain Medicine, Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada.
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Canada.
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Liao Z, Li J, Miao L, Huang Z, Huang W, Liu Y, Li Y. Inhibition of RhoA Activity Does Not Rescue Synaptic Development Abnormalities and Long-Term Cognitive Impairment After Sevoflurane Exposure. Neurochem Res 2021; 46:468-481. [PMID: 33237472 DOI: 10.1007/s11064-020-03180-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 11/09/2020] [Accepted: 11/12/2020] [Indexed: 12/23/2022]
Abstract
General anesthetics interfere with dendritic development and synaptogenesis, resulting in cognitive impairment in the developing animals. RhoA signal pathway plays important roles in dendritic development by regulating cytoskeleton protein such as tubulin and actin. However, it's not clear whether RhoA pathway is involved in inhaled general anesthetics sevoflurane-induced synaptic development abnormalities and long-term cognitive dysfunction. Rats at postnatal day 7 (PND7) were injected intraperitoneally with RhoA pathway inhibitor Y27632 or saline 20 min before exposed to 2.8% sevoflurane for 4 h. The apoptosis-related proteins and RhoA/CRMP2 pathway proteins in the hippocampus were measured 6 h after sevoflurane exposure. Cognitive functions were evaluated by the open field test on PND25 rats and contextual fear conditioning test on PND32-33 rats. The dendritic morphology and density of dendritic spines in the pyramidal neurons of hippocampus were determined by Golgi staining and the synaptic plasticity-related proteins were also measured on PND33 rats. Long term potentiation (LTP) from hippocampal slices was recorded on PND34-37 rats. Sevoflurane induced caspase-3 activation, decreased the ratio of Bcl-2/Bax and increased TUNEL-positive neurons in hippocampus of PND7 rats, which were attenuated by inhibition of RhoA. However, sevoflurane had no significant effects on activity of RhoA/CRMP2 pathway. Sevoflurane disturbed dendritic morphogenesis, reduced the number of dendritic spines, decreased proteins expression of PSD-95, drebrin and synaptophysin, inhibited LTP in hippocampal slices and impaired memory ability in the adolescent rats, while inhibition of RhoA activity did not rescue the changes above induced by sevoflurane. RhoA signal pathway did not participate in sevoflurane-induced dendritic and synaptic development abnormalities and cognitive dysfunction in developing rats.
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Affiliation(s)
- Zhaoxia Liao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Junhua Li
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Liping Miao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Zeqi Huang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Wujian Huang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yafang Liu
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yujuan Li
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, China.
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Regulation of CRMP2 by Cdk5 and GSK-3β participates in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats. Toxicol Lett 2021; 341:68-79. [PMID: 33548343 DOI: 10.1016/j.toxlet.2021.01.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 01/18/2021] [Accepted: 01/31/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND General anesthetics such as sevoflurane interfere with dendritic development and synaptogenesis, resulting in cognitive impairment. The collapsin response mediator protein2 (CRMP2) plays important roles in dendritic development and synaptic plasticity and its phosphorylation is regulated by cycline dependent kinase-5 (Cdk5) and glycogen synthase kinase-3β (GSK-3β). Here we investigated whether Cdk5/CRMP2 or GSK-3β/CRMP2 pathway is involved in sevoflurane-induced developmental neurotoxicity. METHODS Rats at postnatal day 7 (PND7) were i.p. injected with Cdk5 inhibitor roscovitine, GSK-3β inhibitor SB415286 or saline 20 min. before exposure to 2.8% sevoflurane for 4 h. Western-blotting was applied to measure the expression of Cdk5/CRMP2 and GSK-3β/CRMP2 pathway proteins in the hippocampus 6 h after the sevoflurane exposure. When rats grew to adolescence (from PND25), they were tested for open-field and contextual fear conditioning, and then long term potentiation (LTP) from hippocampal slices was recorded, and morphology of pyramidal neuron was examined by Golgi staining and synaptic plasticity-related proteins expression in hippocampus were measured by western-blotting. In another batch of experiment, siRNA-CRMP2 or vehicle control was injected into hippocampus on PND5. RESULTS Sevoflurane activated Cdk5/CRMP2 and GSK-3β/CRMP2 pathways in the hippocampus of neonatal rats, reduced dendritic length, branches and the density of dendritic spine in pyramidal neurons. It also reduced the expressions of PSD-95, drebrin and synaptophysin in hippocampus, impaired memory ability of rats and inhibited LTP in hippocampal slices. All the impairment effects by sevoflurane were attenuated by pretreatment with inhibitor of Cdk5 or GSK-3β. Furthermore, rat transfected with siRNA-CRMP2 eliminated the neuroprotective effects of Cdk5 or GSK-3β blocker in neurobehavioral and LTP tests. CONCLUSION Cdk5/CRMP2 and GSK-3β/CRMP2 pathways participate in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats.
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Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats. Anesthesiology 2020; 133:852-866. [PMID: 32930727 DOI: 10.1097/aln.0000000000003437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. METHODS Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). RESULTS Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). CONCLUSIONS Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity. EDITOR’S PERSPECTIVE
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Liu F, Gong B, Gu Q, Liu S, Fogle CM, Patterson TA, Hanig JP, Slikker W, Wang C. Application of microRNA profiling to understand sevoflurane-induced adverse effects on developing monkey brain. Neurotoxicology 2020; 81:172-179. [PMID: 33045284 DOI: 10.1016/j.neuro.2020.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/06/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
We have described that prolonged sevoflurane exposure at a clinically-relevant concentration of 2.5 % caused neuronal cell death in the developing monkey brain. Postnatal day 5 or 6 rhesus monkeys (n = 3) were exposed to 2.5 % sevoflurane for 8 h. Monkeys kept at environmental conditions in the procedure room served as controls (n = 3). Brain tissues were harvested four hours after sevoflurane exposure for histological analysis, and RNA or protein extraction. MicroRNA (miRNA) profiling on the frontal cortex of monkey brains was performed using next-generation sequencing. 417 miRNAs were identified in the frontal cortex, where most neuronal cell death was observed. 7 miRNAs were differentially expressed in frontal cortex after sevoflurane exposure. Five of these were expressed at significantly lower levels than controls and the other two miRNAs were expressed significantly higher. These differentially expressed miRNAs (DEMs) were then loaded to the Ingenuity Pathway Analysis database for pathway analysis, in which targeting information was available for 5 DEMs. The 5 DEMs target 2,919 mRNAs which are involved in pathways that contribute to various cellular functions. Of note, 78 genes that are related to axon guidance signaling were targeted, suggesting that development of the neural circuit may be affected after sevoflurane exposure. Such changes may have long-term effects on brain development and function. These findings are supplementary to our previous observations and provide more evidence for better understanding the adverse effects of sevoflurane on the developing brain after an 8 -h exposure.
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Affiliation(s)
- Fang Liu
- Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, United States.
| | - Binsheng Gong
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Qiang Gu
- Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Shuliang Liu
- Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Charles Matthew Fogle
- Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Tucker A Patterson
- Office of Director, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Joseph P Hanig
- Office of Pharmaceutical Quality, Center for Drug Evaluation and Research/FDA, Silver Spring, MD, United States
| | - William Slikker
- Office of Director, National Center for Toxicological Research/FDA, Jefferson, AR, United States
| | - Cheng Wang
- Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR, United States.
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Gupta A, Gairola S, Gupta N. Safety of anesthetic exposure on the developing brain - Do we have the answer yet? J Anaesthesiol Clin Pharmacol 2020. [PMID: 33013026 DOI: 10.4103/joacp.joacp_229_19.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
During the past two decades, a vast number of studies done on rodents and nonhuman primates have implicated general anesthetic exposure of developing brains in producing neurotoxicity leading to various structural and functional neurological abnormalities with cognitive and behavioral deficits later in life. However, it is still unclear whether these findings translate to children and whether single exposure to anesthesia in childhood can have long-term neuro-developmental risks. Considering the fact that a large number of healthy young children are undergoing elective surgery under general anesthesia globally, any such potential neurocognitive risk of pediatric anesthesia is a serious public health issue and is therefore important to understand. This review aims to assess the current preclinical and clinical evidence related to anesthetic neurotoxicity.
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Affiliation(s)
- Anju Gupta
- Department of Anesthesiology, Pain and Critical Care, AIIMS, New Delhi, India
| | - Shruti Gairola
- Department of Onco-Anesthesiology and Palliative Care, DRBRAIRCH, AIIMS, Delhi, India
| | - Nishkarsh Gupta
- Department of Onco-Anesthesiology and Palliative Care, DRBRAIRCH, AIIMS, Delhi, India
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Zhang J, Dong Y, Lining Huang, Xu X, Liang F, Soriano SG, Zhang Y, Xie Z. Interaction of Tau, IL-6 and mitochondria on synapse and cognition following sevoflurane anesthesia in young mice. Brain Behav Immun Health 2020; 8:100133. [PMID: 34589883 PMCID: PMC8474534 DOI: 10.1016/j.bbih.2020.100133] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 02/07/2023] Open
Abstract
Tau phosphorylation is associated with cognitive impairment in young mice. However, the underlying mechanism and targeted interventions remain mostly unknown. We set out to determine the potential interactions of Tau, interleukin 6 (IL-6) and mitochondria following treatment of anesthetic sevoflurane and to assess their influences on synapse number and cognition in young mice. Sevoflurane (3% for 2 h) was given to wild-type, Tau knockout, IL-6 knockout, and cyclophilin D (CypD) knockout mice on postnatal (P) day 6, 7 and 8. We measured amounts of phosphorylated Tau, IL-6, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, postsynaptic density 95 (PSD-95), synaptophysin, N-cadherin, synapse number, and cognitive function in the mice, employing Western blot, electron microscope and Morris water maze among others. Here we showed that sevoflurane increased Tau phosphorylation and caused IL-6 elevation, mitochondrial dysfunction, synaptic loss and cognitive impairment in young wild-type, but not Tau knockout, mice. In young IL-6 knockout mice, sevoflurane increased Tau phosphorylation but did not cause mitochondrial dysfunction, synaptic loss or cognitive impairment. Finally, sevoflurane increased Tau phosphorylation and IL-6 amount, but did not induce synaptic loss and cognitive impairment, in young CypD knockout mice or WT mice pretreated with idebenone, an analog of co-enzyme Q10. In conclusion, sevoflurane increased Tau phosphorylation, which caused IL-6 elevation, leading to mitochondrial dysfunction in young mice. Such interactions caused synaptic loss and cognitive impairment in the mice. Idebenone mitigated sevoflurane-induced cognitive impairment in young mice. These studies would promote more research to study Tau in young mice.
Research in context.
Evidence before this study
Tau, a microtubule-associated protein that is predominantly expressed inside neurons, is associated with microtubule assembly and function. Tau phosphorylation, aggregation and spread all serve as the pathogenesis of age-dependent neurodegeneration in the old brain, as well as the neuropathogenesis of Alzheimer’s disease. However, the effects of Tau on the cellular changes and the function of the young brain are undetermined. Our previous studies showed that anesthetic sevoflurane induced Tau phosphorylation, IL-6 elevation, mitochondrial dysfunction and synaptic loss in brain tissues of neonatal mice, as well as cognitive impairment in the mice. However, the potential interactions of the Tau phosphorylation, IL-6 elevation and mitochondrial dysfunction and the influences of these interactions on synapse number and cognitive function in neonatal mice remains largely unknown. Added value of study
Employing sevoflurane as a clinically relevant tool, and using the approaches including wild-type, Tau, IL-6, and CypD knockout neonatal mice, the present studies showed that Tau phosphorylation caused IL-6 elevation, which induced mitochondrial dysfunction, leading to synaptic loss and cognitive impairment in the neonatal mice. Idebenone, a synthetic analog of coenzyme Q10, mitigated the sevoflurane-induced cognitive impairment in the neonatal mice. Implications of all the available evidence
These findings demonstrated the role of Tau phosphorylation in cognitive impairment in neonatal mice, revealed the effects of the interactions of Tau phosphorylation, IL-6 elevation and mitochondrial dysfunction on the synapse number and cognitive function in the mice, and identified potential targeted intervention of the cognitive impairment in the neonatal mice.
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Affiliation(s)
- Jie Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.,Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA
| | - Yuanlin Dong
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA
| | - Lining Huang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA.,Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, PR China
| | - Xiaoming Xu
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA.,Department of Forensic Clinical Medicine, School of Forensic Medicine, China Medical University, Shenyang, PR China
| | - Feng Liang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA
| | - Sulpicio G Soriano
- Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Yiying Zhang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA
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Dexmedetomidine Attenuates Neurotoxicity in Developing Rats Induced by Sevoflurane through Upregulating BDNF-TrkB-CREB and Downregulating ProBDNF-P75NRT-RhoA Signaling Pathway. Mediators Inflamm 2020; 2020:5458061. [PMID: 32655312 PMCID: PMC7322616 DOI: 10.1155/2020/5458061] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/23/2020] [Indexed: 12/22/2022] Open
Abstract
To investigate the mechanism dexmedetomidine in relieving the neurotoxicity of a developing brain induced by sevoflurane. Sprague-Dawley rats, 6 days old, were randomly divided into three groups. Rats in the control group were inhaled with air after injection of normal saline; rats in the sevoflurane group were injected with normal saline and inhaled with 3% sevoflurane for 2 h in three consecutive day; rats in the dexmedetomidine group were inhaled with 3% sevoflurane after intraperitoneal injection of dexmedetomidine 25 μg/kg. WB results showed that mBDNF, pTrkB/TrkB, and CREB were significantly decreased in the hippocampus of the sevoflurane group, which are significantly upregulated in the dexmedetomidine group. In the sevoflurane group, proBDNF, P75NRT, and RhoA were significantly increased, which were significantly lower than those in the dexmedetomidine group than those in the sevoflurane group. The expression BDNF was downregulated in the sevoflurane group, while the proBDNF was upregulated in the sevoflurane group. In the Morris water maze test, the escape latency of the sevoflurane group was significantly prolonged. In sevoflurane groups, the number of crossing platform was significantly reduced, the synaptic protein decreased significantly, and this effect was reversed in rats of the dexmedetomidine group. Dexmedetomidine could reduce synaptic plasticity decline in developing rats induced by sevoflurane, through downregulating the proBDNF-p75NTR-RhoA pathway and upregulating BDNF-TrkB-CREB.
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Foubert R, Devroe S, Foubert L, Van de Velde M, Rex S. Anesthetic neurotoxicity in the pediatric population: a systematic review of the clinical evidence. ACTA ANAESTHESIOLOGICA BELGICA 2020. [DOI: 10.56126/71.2.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
Abstract
Background: Exposure to general anesthesia (GA) in early life is known to be neurotoxic to animals.
Objectives: To evaluate the risk of GA inducing long-term neurodevelopmental deficits in human children.
Design: Systematic review.
Methods: We included observational and randomized studies that compared the long-term neurodevelopment of postnatal children exposed to GA to the long-term neurodevelopment of children not exposed to GA. We searched MEDLINE, Embase and Web of Science for relevant studies published in the year 2000 or later. We screened all the identified studies on predetermined inclusion and exclusion criteria. A risk of bias assessment was made for each included study. We identified 9 neurodevelopmental domains for which a sub-analysis was made: intelligence; memory; learning; language/speech; motor function; visuospatial skills; development/emotions/behavior; ADHD/attention; autistic disorder.
Results: We included 26 studies involving 605.391 participants. Based on AHRQ-standards 11 studies were of poor quality, 7 studies were of fair quality and 8 studies were of good quality. The major causes of potential bias were selection and comparability bias. On 2 neurodevelopmental domains (visuospatial skills and autistic disorder), the available evidence showed no association with exposure to GA. On 7 other neurodevelopmental domains, the available evidence showed mixed results. The 4 studies that used a randomized or sibling-controlled design showed no association between GA and neurodevelopmental deficits in their primary endpoints.
Limitations: The absence of a meta-analysis and funnel plot.
Conclusions: Based on observational studies, we found an association between GA in childhood and neuro-developmental deficits in later life. Randomized and sibling-matched observational studies failed to show the same association and therefore no evidence of a causal relationship exists at present. Since GA seems to be a marker, but not a cause of worse neurodevelopment, we argue against delaying or avoiding interventional or diagnostic procedures requiring GA in childhood based on the argument of GA-induced neurotoxicity.
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Gupta A, Gairola S, Gupta N. Safety of anesthetic exposure on the developing brain - Do we have the answer yet? J Anaesthesiol Clin Pharmacol 2020; 36:149-155. [PMID: 33013026 PMCID: PMC7480296 DOI: 10.4103/joacp.joacp_229_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 08/31/2019] [Indexed: 12/23/2022] Open
Abstract
During the past two decades, a vast number of studies done on rodents and nonhuman primates have implicated general anesthetic exposure of developing brains in producing neurotoxicity leading to various structural and functional neurological abnormalities with cognitive and behavioral deficits later in life. However, it is still unclear whether these findings translate to children and whether single exposure to anesthesia in childhood can have long-term neuro-developmental risks. Considering the fact that a large number of healthy young children are undergoing elective surgery under general anesthesia globally, any such potential neurocognitive risk of pediatric anesthesia is a serious public health issue and is therefore important to understand. This review aims to assess the current preclinical and clinical evidence related to anesthetic neurotoxicity.
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Affiliation(s)
- Anju Gupta
- Department of Anesthesiology, Pain and Critical Care, AIIMS, New Delhi, India
| | - Shruti Gairola
- Department of Onco-Anesthesiology and Palliative Care, DRBRAIRCH, AIIMS, Delhi, India
| | - Nishkarsh Gupta
- Department of Onco-Anesthesiology and Palliative Care, DRBRAIRCH, AIIMS, Delhi, India
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Tang X, Zhao Y, Zhou Z, Yan J, Zhou B, Chi X, Luo A, Li S. Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9018624. [PMID: 32148659 PMCID: PMC7049870 DOI: 10.1155/2020/9018624] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/14/2019] [Accepted: 01/18/2020] [Indexed: 02/07/2023]
Abstract
Various lines of evidence suggest that neonatal exposure to general anesthetics, especially repeatedly, results in neuropathological brain changes and long-term cognitive impairment. Although progress has been made in experimental models, the exact mechanism of GA-induced neurotoxicity in the developing brain remains to be clarified. Sirtuin 1 (SIRT1) plays an important role in synaptic plasticity and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. However, the role of SIRT1 in GA-induced neurotoxicity is unclear to date. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampi of developing mice exposed to sevoflurane. Furthermore, the SIRT1 inhibition in hippocampi was associated with brain-derived neurotrophic factor (BDNF) downregulation modulated by methyl-cytosine-phosphate-guanine-binding protein 2 (MeCP2) and cAMP response element-binding protein (CREB). Pretreatment of neonatal mice with resveratrol nearly reversed the reduction in hippocampal SIRT1 expression, which increased the expression of BDNF in developing mice exposed to sevoflurane. Moreover, changes in the levels of CREB and MeCP2, which were considered to interact with BDNF promoter IV, were also rescued by resveratrol. Furthermore, resveratrol improved the cognitive performance in the Morris water maze test of the adult mice with exposure to sevoflurane in the neonatal stage, without changing motor function in the open field test. Taken together, our findings suggested that SIRT1 deficiency regulated BDNF signaling via regulation of the epigenetic activity of MeCP2 and CREB, and resveratrol might be a promising agent for mitigating sevoflurane-induced neurotoxicity in developing mice.
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Affiliation(s)
- Xiaole Tang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Yilin Zhao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Zhiqiang Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Jing Yan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Biyun Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Xiaohui Chi
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Ailin Luo
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
| | - Shiyong Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei, China
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Hypoxia, hypercarbia, and mortality reporting in studies of anaesthesia-related neonatal neurodevelopmental delay in rodent models. Eur J Anaesthesiol 2020; 37:70-84. [DOI: 10.1097/eja.0000000000001105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Li R, Li D, Wu C, Ye L, Wu Y, Yuan Y, Yang S, Xie L, Mao Y, Jiang T, Li Y, Wang J, Zhang H, Li X, Xiao J. Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration. Theranostics 2020; 10:1649-1677. [PMID: 32042328 PMCID: PMC6993217 DOI: 10.7150/thno.40919] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 10/27/2019] [Indexed: 12/12/2022] Open
Abstract
Rationale: Autophagy in Schwann cells (SCs) is crucial for myelin debris degradation and clearance following peripheral nerve injury (PNI). Nerve growth factor (NGF) plays an important role in reconstructing peripheral nerve fibers and promoting axonal regeneration. However, it remains unclear if NGF effect in enhancing nerve regeneration is mediated through autophagic clearance of myelin debris in SCs. Methods: In vivo, free NGF solution plus with/without pharmacological inhibitors were administered to a rat sciatic nerve crush injury model. In vitro, the primary Schwann cells (SCs) and its cell line were cultured in normal medium containing NGF, their capable of swallowing or clearing degenerated myelin was evaluated through supplement of homogenized myelin fractions. Results: Administration of exogenous NGF could activate autophagy in dedifferentiated SCs, accelerate myelin debris clearance and phagocytosis, as well as promote axon and myelin regeneration at early stage of PNI. These NGF effects were effectively blocked by autophagy inhibitors. In addition, inhibition of the p75 kD neurotrophin receptor (p75NTR) signal or inactivation of the AMP-activated protein kinase (AMPK) also inhibited the NGF effect as well. Conclusions: NGF effect on promoting early nerve regeneration is closely associated with its accelerating autophagic clearance of myelin debris in SCs, which probably regulated by the p75NTR/AMPK/mTOR axis. Our studies thus provide strong support that NGF may serve as a powerful pharmacological therapy for peripheral nerve injuries.
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Clausen NG, Hansen TG, Disma N. Anesthesia Neurotoxicity in the Developing Brain: Basic Studies Relevant for Neonatal or Perinatal Medicine. Clin Perinatol 2019; 46:647-656. [PMID: 31653300 DOI: 10.1016/j.clp.2019.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Diagnostic and invasive procedures in premature infants may require general anesthesia. General anesthetics interfere with the development of the immature animal brain. Accelerated apoptosis, disturbed synaptogenesis, and cytoarchitecture are among the mechanisms suspected to underlie this phenomenon. The implications for humans are unknown. This article presents current suspected mechanisms of anesthesia-induced neurotoxicity and elaborates on the difficulties in translating results from animal research to human. Ethical considerations limit the conduct of such experiments in human neonates, but the use of animal models is still considered feasible. Vulnerable periods in brain development need further identification as do neurotoxic and neuroprotective interventions.
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Affiliation(s)
- Nicola Groes Clausen
- Department of Anesthesiology and Intensive Care, Odense University Hospital, J.B. Winsløwsvej 4, Odense C 5000, Denmark
| | - Tom G Hansen
- Department of Anesthesiology and Intensive Care - Pediatrics, Odense University Hospital, J.B. Winsløwsvej 4, Odense C 5000, Denmark; Department of Clinical Research - Anesthesiology, University of Southern Denmark, Odense C 5000, Denmark
| | - Nicola Disma
- Department of Anesthesia, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, Genoa 16100, Italy.
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General anesthetic neurotoxicity in the young: Mechanism and prevention. Neurosci Biobehav Rev 2019; 107:883-896. [PMID: 31606415 DOI: 10.1016/j.neubiorev.2019.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/27/2019] [Accepted: 10/04/2019] [Indexed: 12/17/2022]
Abstract
General anesthesia (GA) is usually considered to safely induce a reversible unconscious state allowing surgery to be performed without pain. A growing number of studies, in particular pre-clinical studies, however, demonstrate that general anesthetics can cause neuronal death and even long-term neurological deficits. Herein, we report our literature review and meta-analysis data of the neurological outcomes after anesthesia in the young. We also review available mechanistic and epigenetic data of GA exposure related to cognitive impairment per se and the potential preventive strategies including natural herbal compounds to attenuate those side effects. In summary, anesthetic-induced neurotoxicity may be treatable and natural herbal compounds and other medications may have great potential for such use but warrants further study before clinical applications can be initiated.
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Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence? Anesthesiology 2019; 128:832-839. [PMID: 29271804 DOI: 10.1097/aln.0000000000002047] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Recently, the U.S. Food and Drug Administration issued an official warning to all practicing physicians regarding potentially detrimental behavioral and cognitive sequelae of an early exposure to general anesthesia during in utero and in early postnatal life. The U.S. Food and Drug Administration concern is focused on children younger than three years of age who are exposed to clinically used general anesthetics and sedatives for three hours or longer. Although human evidence is limited and controversial, a large body of scientific evidence gathered from several mammalian species demonstrates that there is a potential foundation for concern. Considering this new development in public awareness, this review focuses on nonhuman primates because their brain development is the closest to humans in terms of not only timing and duration, but in terms of complexity as well. The review compares those primate findings to previously published work done with rodents.
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Defining the Vulnerability Window of Anesthesia-Induced Neuroapoptosis in Developing Dentate Gyrus Granule Cells - A Transgenic Approach Utilizing POMC-EGFP Mice. Neuroscience 2019; 415:59-69. [PMID: 31301366 DOI: 10.1016/j.neuroscience.2019.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 05/20/2019] [Accepted: 07/02/2019] [Indexed: 11/22/2022]
Abstract
Exposure to commonly used anesthetics is associated with widespread neuroapoptosis in neonatal animals. Vulnerability of developing hippocampal dentate gyrus granule cells to anesthetic neurotoxicity peaks approximately 2 weeks after cell birth, as measured by bromodeoxyuridine birth dating, regardless of the age of the animal. The present study examined whether the vulnerable window can be further characterized by utilizing a transgenic approach. Proopiomelanocortin enhanced green fluorescent protein (POMC-EGFP) mice (postnatal day 21) were exposed to 3% sevoflurane for 6 h. Following exposure, cleaved caspase 3, expression of EGFP and differential maturational markers were quantified and compared with unanesthetized littermates. Electrophysiological properties of EGFP+ and EGFP- cells in the subgranular zone and the inner half of the granule cell layer were recorded by whole-cell patch-clamp. We found that sevoflurane significantly increased apoptosis of POMC-EGFP+ granule cells that accounted for approximate 1/3 of all apoptotic cells in dentate gyrus. Apoptotic EGFP- granule cells more frequently expressed the immature neuronal marker calretinin (75.4% vs 45.0%, P < 0.001) and less frequently the late progenitor marker NeuroD1 (21.9% vs 87.9%, P < 0.001) than EGFP+ granule cells. Although EGFP- granule cells were more mature in immunostaining than EGFP+ granule cells, their electrophysiological properties partially overlapped in terms of input resistance, resting membrane potential and action potential amplitude. Our results revealed the POMC stage, when GABA acts as an excitatory neurotransmitter, only partly captures susceptibility to anesthetic neurotoxicity, suggesting the vulnerable window of anesthesia-induced neuroapoptosis extends from the end of POMC+ stage to the post-POMC+ stage when depolarizing glutamatergic inputs emerge.
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41
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Huang B, Huang H, Zhang Z, Liu Z, Luo J, Liu M, Luo T. Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8. CNS Neurosci Ther 2019; 25:612-620. [PMID: 30676695 PMCID: PMC6488878 DOI: 10.1111/cns.13090] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/13/2018] [Accepted: 11/15/2018] [Indexed: 02/05/2023] Open
Abstract
AIMS It is well established that exposure of common anesthetic isoflurane in early life can induce neuronal apoptosis and long-lasting cognitive deficit, but the underlying mechanisms were not well understood. The cell cycle protein Cyclin B1 plays an important role in the survival of postmitotic neurons. In the present study, we investigated whether cyclin B1-mediated cell cycle activation pathway is a contributing factor in developmental isoflurane neurotoxicity. METHODS Postnatal day 7 mice were exposed to 1.2% isoflurane for 6 hours. CR8 (a selective inhibitor of cyclin-dependent kinases) was applied before isoflurane treatment. Brain samples were collected 6 hours after discontinuation of isoflurane, for determination of neurodegenerative biomarkers and cell cycle biomarkers. RESULTS We found that isoflurane exposure leads to upregulated expression of cell cycle-related biomarkers Cyclin B1, Phospho-CDK1(Thr-161), Phospho-n-myc and downregulated Phospho-CDK1 (Tyr-15). In addition, isoflurane induced increase in Bcl-xL phosphorylation, cytochrome c release, and caspase-3 activation that resulted in neuronal cell death. Systemic administration of CR8 attenuated isoflurane-induced cell cycle activation and neurodegeneration. CONCLUSION These findings suggest the role of cell cycle activation to be a pathophysiological mechanism for isoflurane-induced apoptotic cell death and that treatment with cell cycle inhibitors may provide a possible therapeutic target for prevention of developmental anesthetic neurotoxicity.
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Affiliation(s)
- Bao‐Yi Huang
- Department of AnesthesiologyPeking University Shenzhen HospitalShenzhenChina
- Shantou University Medical CollegeShantouGuangdongP.R. China
| | - Hong‐Bing Huang
- Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouChina
| | - Zhi‐Jing Zhang
- Department of AnesthesiologyPeking University Shenzhen HospitalShenzhenChina
- Shantou University Medical CollegeShantouGuangdongP.R. China
| | - Zhi‐Gang Liu
- Department of AnesthesiologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Jun Luo
- Department of PathologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Min Liu
- Health and Family Planning Capacity Building and Continuing Education Center of Shenzhen MunicipalityShenzhenChina
| | - Tao Luo
- Department of AnesthesiologyPeking University Shenzhen HospitalShenzhenChina
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General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity. Neuropharmacology 2019; 150:153-163. [PMID: 30926450 DOI: 10.1016/j.neuropharm.2019.03.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 01/25/2023]
Abstract
Accumulating evidence indicates that exposure to general anesthetics during infancy and childhood can cause persistent cognitive impairment, alterations in synaptic plasticity, and, to a lesser extent, increased incidence of behavioral disorders. Unfortunately, the developmental parameters of susceptibility to general anesthetics are not well understood. Adolescence is a critical developmental period wherein multiple late developing brain regions may also be vulnerable to enduring general anesthetic effects. Given the breadth of the adolescent age span, this group potentially represents millions more individuals than those exposed during early childhood. In this study, isoflurane exposure within a well-characterized adolescent period in Sprague-Dawley rats elicited immediate and persistent anxiety- and impulsive-like responding, as well as delayed cognitive impairment into adulthood. These behavioral abnormalities were paralleled by atypical dendritic spine morphology in the prefrontal cortex (PFC) and hippocampus (HPC), suggesting delayed anatomical maturation, and shifts in inhibitory function that suggest hypermaturation of extrasynaptic GABAA receptor inhibition. Preventing this hypermaturation of extrasynaptic GABAA receptor-mediated function in the PFC selectively reversed enhanced impulsivity resulting from adolescent isoflurane exposure. Taken together, these data demonstrate that the developmental window for susceptibility to enduring untoward effects of general anesthetics may be much longer than previously appreciated, and those effects may include affective behaviors in addition to cognition.
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Tu Y, Liang Y, Xiao Y, Lv J, Guan R, Xiao F, Xie Y, Xiao Q. Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways. Drug Des Devel Ther 2019; 13:695-706. [PMID: 30858699 PMCID: PMC6387615 DOI: 10.2147/dddt.s188436] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Propofol is a commonly used general anesthetic for the induction and maintenance of anesthesia and critical care sedation in children, which may add risk to poor neurodevelopmental outcome. We aimed to evaluate the effect of propofol toward primary hippocampal neurons in vitro and the possibly neuroprotective effect of dexmedetomidine pretreatment, as well as the underlying mechanism. MATERIALS AND PROCEDURES Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using a transmission electron microscope and flow cytometry analyses. Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR. The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting. RESULTS Propofol significantly reduced cell viability, induced neuronal apoptosis, and downregulated the expression of the BDNF mRNA and the levels of the phospho-Erk1/2 (p-Erk1/2), phospho-CREB (p-CREB), and BDNF proteins. The dexmedetomidine pretreatment increased neuronal viability and alleviated propofol-induced neuronal apoptosis and rescued the propofol-induced downregulation of both the BDNF mRNA and the levels of the p-Erk1/2, p-CREB, and BDNF proteins. However, this neuroprotective effect was abolished by PD98059, H89, and KG501, further preventing the dexmedetomidine pretreatment from rescuing the propofol-induced downregulation of the BDNF mRNA and p-Erk1/2, p-CREB, and BDNF proteins. CONCLUSION Dexmedetomidine alleviates propofol-induced cytotoxicity toward primary hippocampal neurons in vitro, which correlated with the activation of Erk1/2/CREB/BDNF signaling pathways.
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Affiliation(s)
- Youbing Tu
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Yubing Liang
- Department of Anesthesiology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yong Xiao
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Jing Lv
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Ruicong Guan
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Fei Xiao
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Yubo Xie
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
| | - Qiang Xiao
- Department of Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China,
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Schaefer ML, Wang M, Perez PJ, Coca Peralta W, Xu J, Johns RA. Nitric Oxide Donor Prevents Neonatal Isoflurane-induced Impairments in Synaptic Plasticity and Memory. Anesthesiology 2019; 130:247-262. [PMID: 30601214 PMCID: PMC6538043 DOI: 10.1097/aln.0000000000002529] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC Some general anesthetics have been shown to have adverse effects on neuronal development that affect neural function and cognitive behavior.Clinically relevant concentrations of inhalational anesthetics inhibit the postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domain-mediated protein-protein interaction between PSD-95 or PSD-93 and N-methyl-D-aspartate receptors or neuronal NO synthase. WHAT THIS ARTICLE TELLS US THAT IS NEW Neonatal PSD-95 PDZ2WT peptide treatment mimics the effects of isoflurane (~1 minimum alveolar concentration) by altering dendritic spine morphology, neural plasticity, and memory without inducing detectable increases in apoptosis or changes in synaptic density.These results indicate that a single dose of isoflurane (~1 minimum alveolar concentration) or PSD-95 PDZ2WT peptide alters dendritic spine architecture and functions important for cognition in the developing brain. This impairment can be prevented by administration of the NO donor molsidomine. BACKGROUND In humans, multiple early exposures to procedures requiring anesthesia constitute a significant risk factor for development of learning disabilities and disorders of attention. In animal studies, newborns exposed to anesthetics develop long-term deficits in cognition. Previously, our laboratory showed that postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domains may serve as a molecular target for inhaled anesthetics. This study investigated a role for PDZ interactions in spine development, plasticity, and memory as a potential mechanism for early anesthetic exposure-produced cognitive impairment. METHODS Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 PDZ2WT peptide. Apoptosis, hippocampal dendritic spine changes, synapse density, long-term potentiation, and cognition functions were evaluated (n = 4 to 18). RESULTS Exposure of postnatal day 7 mice to isoflurane or PSD-95 PDZ2WT peptide causes a reduction in long thin spines (median, interquartile range [IQR]: wild type control [0.54, 0.52 to 0.86] vs. wild type isoflurane [0.31, 0.16 to 0.38], P = 0.034 and PDZ2MUT [0.86, 0.67 to 1.0] vs. PDZ2WT [0.55, 0.53 to 0.59], P = 0.028), impairment in long-term potentiation (median, IQR: wild type control [123, 119 to 147] and wild type isoflurane [101, 96 to 118], P = 0.049 and PDZ2MUT [125, 119 to 131] and PDZ2WT [104, 97 to 107], P = 0.029), and deficits in acute object recognition (median, IQR: wild type control [79, 72 to 88] vs. wild type isoflurane [63, 55 to 72], P = 0.044 and PDZ2MUT [81, 69 to 84] vs. PDZ2WT [67, 57 to 77], P = 0.039) at postnatal day 21 without inducing detectable differences in apoptosis or changes in synaptic density. Impairments in recognition memory and long-term potentiation were preventable by introduction of a NO donor. CONCLUSIONS Early disruption of PDZ domain-mediated protein-protein interactions alters spine morphology, synaptic function, and memory. These results support a role for PDZ interactions in early anesthetic exposure-produced cognitive impairment. Prevention of recognition memory and long-term potentiation deficits with a NO donor supports a role for the N-methyl-D-aspartate receptor/PSD-95/neuronal NO synthase pathway in mediating these aspects of isoflurane-induced cognitive impairment.
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Affiliation(s)
- Michele L Schaefer
- From the Department Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
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Jevtovic-Todorovic V. Anaesthesia-induced developmental neurotoxicity: reality or fiction? Br J Anaesth 2018; 119:455-457. [PMID: 28969321 DOI: 10.1093/bja/aex161] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Affiliation(s)
- V Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA
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Johnson SC, Pan A, Li L, Sedensky M, Morgan P. Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies. Neurotoxicol Teratol 2018; 71:22-31. [PMID: 30472095 DOI: 10.1016/j.ntt.2018.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/02/2018] [Accepted: 11/21/2018] [Indexed: 12/12/2022]
Abstract
Volatile anesthetics are widely used in human medicine and generally considered to be safe in healthy individuals. In recent years, the safety of volatile anesthesia in pediatric patients has been questioned following reports of anesthetic induced neurotoxicity in pre-clinical studies. These studies in mice, rats, and primates have demonstrated that exposure to anesthetic agents during early post-natal periods can cause acute neurotoxicity, as well as later-life cognitive defects including deficits in learning and memory. In recent years, the focus of many pre-clinical studies has been on identifying candidate pathways or potential therapeutic targets through intervention trials. These reports have shed light on the mechanisms underlying anesthesia induced neurotoxicity as well as highlighting the challenges of pre-clinical modeling of anesthesia induced neurotoxicity in mice. Here, we summarize the data derived from intervention studies in neonatal mouse models of anesthetic exposure and provide an overview of mechanisms proposed to mediate anesthesia induced neurotoxicity in mice based on these reports. The majority of these studies implicate one of three mechanisms: reactive oxygen species (ROS) mediated stress and signaling, growth/nutrient signaling, or direct neuronal modulation.
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Affiliation(s)
- Simon C Johnson
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America.
| | - Amanda Pan
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America
| | - Li Li
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America; Department of Anesthesiology, University of Washington, Seattle, WA, United States of America
| | - Margaret Sedensky
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America; Department of Anesthesiology, University of Washington, Seattle, WA, United States of America
| | - Philip Morgan
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, United States of America; Department of Anesthesiology, University of Washington, Seattle, WA, United States of America
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Granato A, Dering B. Alcohol and the Developing Brain: Why Neurons Die and How Survivors Change. Int J Mol Sci 2018; 19:ijms19102992. [PMID: 30274375 PMCID: PMC6213645 DOI: 10.3390/ijms19102992] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 09/27/2018] [Accepted: 09/29/2018] [Indexed: 02/06/2023] Open
Abstract
The consequences of alcohol drinking during pregnancy are dramatic and usually referred to as fetal alcohol spectrum disorders (FASD). This condition is one of the main causes of intellectual disability in Western countries. The immature fetal brain exposed to ethanol undergoes massive neuron death. However, the same mechanisms leading to cell death can also be responsible for changes of developmental plasticity. As a consequence of such a maladaptive plasticity, the functional damage to central nervous system structures is amplified and leads to permanent sequelae. Here we review the literature dealing with experimental FASD, focusing on the alterations of the cerebral cortex. We propose that the reciprocal interaction between cell death and maladaptive plasticity represents the main pathogenetic mechanism of the alcohol-induced damage to the developing brain.
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Affiliation(s)
- Alberto Granato
- Department of Psychology, Catholic University, Largo A. Gemelli 1, 20123 Milan, Italy.
| | - Benjamin Dering
- Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK.
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Sachana M, Rolaki A, Bal-Price A. Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol Appl Pharmacol 2018; 354:153-175. [PMID: 29524501 PMCID: PMC6095943 DOI: 10.1016/j.taap.2018.02.024] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 01/06/2023]
Abstract
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.
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Affiliation(s)
| | | | - Anna Bal-Price
- European Commission, Joint Research Centre, Ispra, Italy.
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Sachana M, Rolaki A, Bal-Price A. Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol Appl Pharmacol 2018; 354:153-175. [PMID: 29524501 DOI: 10.1787/5jlsqs5hcrmq-en] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 05/20/2023]
Abstract
The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.
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Affiliation(s)
| | | | - Anna Bal-Price
- European Commission, Joint Research Centre, Ispra, Italy.
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Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes. Sci Rep 2018; 8:10656. [PMID: 30006558 PMCID: PMC6045579 DOI: 10.1038/s41598-018-28874-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 07/02/2018] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate – directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic’s effect with its associated functional change.
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