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Ju LS, Morey T, Gravenstein N, Setlow B, Seubert CN, Martynyuk AE. Effects of Cohabitation on Neurodevelopmental Outcomes in Rats Discordant for Neonatal Exposure to Sevoflurane. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100359. [PMID: 39282654 PMCID: PMC11400603 DOI: 10.1016/j.bpsgos.2024.100359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/03/2024] [Accepted: 07/02/2024] [Indexed: 09/19/2024] Open
Abstract
Background Having a sibling with autism spectrum disorder is a risk factor for autism spectrum disorder. We used a rat model in which the general anesthetic sevoflurane (SEVO) induces autism spectrum disorder-like neurodevelopmental abnormalities to test whether they can be transmitted via cohabitation. Methods Male rat pups from several litters were mixed and randomized to 3 new litter types: SEVO-exposed (SEVO), SEVO-unexposed (control), and equal numbers of SEVO-exposed and SEVO-unexposed (MIXED). After weaning, rats in experiment 1 were housed with littermates in SEVO, control, and MIXED (MIXED-exposed and MIXED-unexposed) pairs. In experiment 2, MIXED-exposed and MIXED-unexposed rats were paired with an unfamiliar naïve cagemate. Corticosterone levels, gene expression, central inflammatory markers (experiment 1), and behavior and corticosterone levels (experiment 2) were assessed in adulthood. Results In experiment 1, compared with control rats, SEVO rats exhibited abnormalities in the hypothalamic-pituitary-adrenal axis, inflammatory markers, oxytocin, arginine vasopressin, and DNA methylation systems. Almost all these measures in MIXED-exposed and MIXED-unexposed rats were statistically indistinguishable from and similar to those in SEVO or control rats, with most measures in MIXED rats being similar to those in SEVO rats. Experiment 2 showed that pairing with unfamiliar, naïve rats after weaning caused MIXED-unexposed and MIXED-exposed rats' behavior to be no different from that of control and SEVO rats, respectively; however, the 2 groups of MIXED rats also did not differ from each other. Conclusions These findings suggest that neurodevelopmental abnormalities can be transmitted to otherwise healthy individuals through interactions during cohabitation; however, subsequent pairing with unfamiliar, naïve cohabitants may weaken this interaction effect.
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Timothy Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Barry Setlow
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
- Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida
| | - Christoph N. Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
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Ionescu MI, Grigoras IF, Ionescu RB, Chitimus DM, Haret RM, Ianosi B, Ceanga M, Zagrean AM. Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen-Glucose Deprivation Conditions. Curr Issues Mol Biol 2024; 46:6223-6236. [PMID: 38921042 PMCID: PMC11202210 DOI: 10.3390/cimb46060371] [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: 05/19/2024] [Revised: 06/12/2024] [Accepted: 06/16/2024] [Indexed: 06/27/2024] Open
Abstract
Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen-glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT's potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT's precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection.
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Affiliation(s)
- Mara Ioana Ionescu
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
| | - Ioana-Florentina Grigoras
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
- Wellcome Centre for Integrative Neuroimaging, Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
| | - Rosana-Bristena Ionescu
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1TN, UK
- NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Diana Maria Chitimus
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
| | - Robert Mihai Haret
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
- Department of Ophthalmology, University Medical Center Gottingen, 37075 Gottingen, Germany
| | - Bogdan Ianosi
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
- Department of Neurology, Stroke Unit, Neuromed Campus, Kepler University Hospital, 4020 Linz, Austria
| | - Mihai Ceanga
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
- Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
| | - Ana-Maria Zagrean
- Department of Functional Sciences, Division of Physiology II-Neuroscience, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (M.I.I.); (I.-F.G.); (R.-B.I.); (D.M.C.); (R.M.H.); (B.I.)
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Rao S, Farhat A, Rakshasbhuvankar A, Athikarisamy S, Ghosh S, Nagarajan L. Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies. Seizure 2023; 111:206-214. [PMID: 37690372 DOI: 10.1016/j.seizure.2023.09.007] [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: 06/22/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 09/12/2023] Open
Abstract
BACKGROUND Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.
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Affiliation(s)
- Shripada Rao
- Neonatal Intensive Care Unit, King Edward Memorial and Perth Children's Hospitals, Perth, Australia; Paediatric Division, Medical School, University of Western Australia, Perth, Australia.
| | - Asifa Farhat
- General Paediatrics, Perth Children's Hospital, Perth, Australia
| | - Abhijeet Rakshasbhuvankar
- Neonatal Intensive Care Unit, King Edward Memorial and Perth Children's Hospitals, Perth, Australia; Paediatric Division, Medical School, University of Western Australia, Perth, Australia
| | - Sam Athikarisamy
- Neonatal Intensive Care Unit, King Edward Memorial and Perth Children's Hospitals, Perth, Australia; Paediatric Division, Medical School, University of Western Australia, Perth, Australia
| | - Soumya Ghosh
- Children's Neuroscience Service, Department of Neurology, Perth Children's Hospital, Perth, Australia; Centre for Neuromuscular and Neurological Disorders, Perron Institute, University of Western Australia, Perth, Australia
| | - Lakshmi Nagarajan
- Paediatric Division, Medical School, University of Western Australia, Perth, Australia; Children's Neuroscience Service, Department of Neurology, Perth Children's Hospital, Perth, Australia
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Chen BZ, Jiang LH, Zhou W, Shang YC, Li F, Liu B. Repeated Sevoflurane Exposure in Neonatal Rats Enhances the Sensitivity to Pain and Traumatic Stress Later in Juvenile Life. J Pain Res 2022; 15:3171-3178. [PMID: 36258761 PMCID: PMC9572549 DOI: 10.2147/jpr.s365253] [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: 03/06/2022] [Accepted: 10/05/2022] [Indexed: 11/16/2022] Open
Abstract
Purposeː Sevoflurane exposure in the neonatal period of rodent animals was reported to be associated with neuroendocrine dysregulations later in life. We tested the hypothesis that repeated sevoflurane exposure in neonatal rats enhances the sensitivity to pain and acute traumatic stress response later in juvenile life and investigated whether the neonatal brain depolarizing γ-aminobutyric acid type A receptor (GABAAR) activity is involved in mediating these abnormalities. Methodsː The postnatal 6 days (P6) Sprague-Dawley male rat pups pretreated with vehicle or the NKCC1 inhibitor, bumetanide, received sequential exposures to 2.1% sevoflurane exposure for 2 hours daily in 3 consecutive days. Resultsː The results showed that repeated exposures to sevoflurane in neonatal rats significantly reduced the paw withdrawal thermal latency (PWTL) at P9, P45. Repeated exposures to sevoflurane in neonatal rats did not significantly affect the basal secretion of serum corticosterone at juvenile period P45, whereas the level of corticosterone for neonatal sevoflurane-exposed rats at P45 was significantly higher than the CON group after subject to conditioned fear traumatic stress (CFTS). The resulting NKCC1/KCC2 mRNA ratio was significantly increased immediately after the neonatal rats received the last sevoflurane exposure, which was alleviated by pretreated with the NKCC1 inhibitor bumetanide. Conclusionː Repeated exposures to sevoflurane in neonatal rats enhanced the sensitivity to pain and acute traumatic stress response in juvenile life. The neonatal brain depolarizing GABAAR activity is involved in mediating these abnormalities.
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Affiliation(s)
- Ben-Zhen Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China,Department of Anesthesiology, Sichuan Provincial Women’s and Children’s Hospital, Chengdu, People’s Republic of China
| | - Li-Hua Jiang
- Department of Operating Room Nursing, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Wenqin Zhou
- Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Yu-Chao Shang
- Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Fang Li
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Bin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China,Correspondence: Bin Liu, Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-13408669172, Email
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Martynyuk AE, Ju LS, Morey TE. The potential role of stress and sex steroids in heritable effects of sevoflurane†. Biol Reprod 2021; 105:735-746. [PMID: 34192761 PMCID: PMC8444702 DOI: 10.1093/biolre/ioab129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/17/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
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Effects of Propofol versus Sevoflurane on Postoperative Pain and Neuroendocrine Stress Response in Oocyte Pickup Patients. Pain Res Manag 2021; 2021:5517150. [PMID: 33936350 PMCID: PMC8055426 DOI: 10.1155/2021/5517150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/18/2021] [Accepted: 03/31/2021] [Indexed: 02/02/2023]
Abstract
Background Pain aggravates the autonomic response to stress and raises neuroendocrine stress hormone levels. We compared the effects of propofol and sevoflurane on postoperative pain and neuroendocrine stress hormones. A prospective, randomized, and controlled trial was conducted with 60 patients. Methods We randomly allocated patients to groups P (remifentanil/propofol, n = 30) and S (remifentanil/sevoflurane, n = 30). Preoperative blood samples were taken to measure serum adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), glucagon, cortisol, aldosterone, and prostaglandin E2 (PGE2) levels. Intraoperatively and postoperatively, clinical parameters were monitored at different time points. The hormone levels were again measured in the follicular fluid and blood postoperatively. Result Demographic data were similar. The preoperative serum aldosterone levels were significantly higher in group P (p=0.001). Preoperative and postoperative serum ACTH, glucagon, cortisol, and PGE2 levels were significantly different in group P (p=0.009, p=0.004, p=0.029, and p=0.002); serum ACTH, glucagon, and PGE2 levels increased while serum cortisol levels decreased postoperatively. In group S, serum CRH and aldosterone levels, both increased in the postoperative period compared to the preoperative (p=0.001, p=0.006). Postoperatively, glucagon and PGE2 levels were both higher in group P than group S (p=0.019, p=0.015). In postoperative follicular fluid, glucagon and PGE2 levels were higher in group P, while cortisol levels were higher in group S (p=0.001, p=0.007, and p=0.001). Conclusion The effects of anesthetic agents were different. In group P, in the preoperative and postoperative evaluation, ACTH, glucagon, and PGE2 increased postoperatively, while cortisol decreased. In group S, aldosterone and CRH increased postoperatively. Glucagon and PG E2 were higher in group P than S, postoperatively.
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Wu Z, Xie C, Kuang H, Wu J, Chen X, Liu H, Liu T. Oxytocin mediates neuroprotection against hypoxic-ischemic injury in hippocampal CA1 neuron of neonatal rats. Neuropharmacology 2021; 187:108488. [PMID: 33556384 DOI: 10.1016/j.neuropharm.2021.108488] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 01/26/2021] [Accepted: 01/31/2021] [Indexed: 12/13/2022]
Abstract
Neonatal hypoxic-ischemic encephalopathy (NHIE) is one of the most prevalent causes of death during the perinatal period. The lack of exposure to oxytocin is associated with NHIE-mediated severe brain injury. However, the underlying mechanism is not fully understood. This study combined immunohistochemistry with electrophysiological recordings of hippocampal CA1 neurons to investigate the role of oxytocin in an in vitro model of hypoxic-ischemic (HI) injury (oxygen and glucose deprivation, OGD) in postnatal day 7-10 rats. Immunohistochemical analysis showed that oxytocin largely reduced the relative intensity of TOPRO-3 staining following OGD in the hippocampal CA1 region. Whole-cell patch-clamp recording revealed that the OGD-induced onset time of anoxic depolarization (AD) was significantly delayed by oxytocin. This protective effect of oxytocin was blocked by pretreatment with [d(CH2)51, Tyr (Me)2, Thr4, Orn8, des-Gly-NH29] vasotocin (dVOT, an oxytocin receptor antagonist) or bicuculline (a GABAA receptor antagonist). Interestingly, oxytocin enhanced inhibitory postsynaptic currents in CA1 pyramidal neurons, which were abolished by tetrodotoxin or dVOT. In contrast, oxytocin had no effect on excitatory postsynaptic currents but induced an inward current in 86% of the pyramidal neurons tested. Taken together, these results demonstrate that oxytocin receptor signaling plays a critical role in attenuating neonatal neural death by facilitating GABAergic transmission, which may help to regulate the excitatory-inhibitory balance in local neuronal networks in NHIE patients.
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Affiliation(s)
- Zhihong Wu
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China
| | - Changning Xie
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China
| | - Haixia Kuang
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China
| | - Jian Wu
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China
| | - Xiao Chen
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China
| | - Huibao Liu
- Department of Pediatrics, Xinyu Maternal and Child Health Hospital, 292 S. Laodong, Xinyu, Jiangxi, 338025, PR China.
| | - Tao Liu
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, 17 St. Yongwaizheng, Nanchang, Jiangxi, 330006, PR China.
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Neag MA, Mitre AO, Catinean A, Mitre CI. An Overview on the Mechanisms of Neuroprotection and Neurotoxicity of Isoflurane and Sevoflurane in Experimental Studies. Brain Res Bull 2020; 165:281-289. [DOI: 10.1016/j.brainresbull.2020.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 12/13/2022]
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Wang J, Yang B, Ju L, Yang J, Allen A, Zhang J, Martynyuk AE. The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats. Front Syst Neurosci 2020; 14:546531. [PMID: 33013333 PMCID: PMC7498728 DOI: 10.3389/fnsys.2020.546531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/14/2020] [Indexed: 01/14/2023] Open
Abstract
Background In rodents, the period of increased vulnerability to the developmental effects of general anesthetics coincides with the period of age-specific organizing (masculinizing) effects of the major female sex hormone 17β-estradiol (E2) in the male brain and excitatory GABA type A receptor (GABAAR) signaling. We studied whether E2 synthesis and excitatory GABAAR signaling are involved in the mediation of the developmental effects of sevoflurane in male rats. Methods Male Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na+-K+-2Cl– (NKCC1) Cl– importer, bumetanide, prior to sevoflurane exposure for 6 h on postnatal (P) day 4, P5, or P6. We tested whether a subsequent exposure of these rats to sevoflurane on P∼10 would cause electroencephalography (EEG)-detectable seizures. We also evaluated their behavior during the elevated plus maze (EPM) test on P∼60, prepulse inhibition (PPI) of acoustic startle responses on P∼70, and corticosterone secretion to physical restraint on P∼80. Results The rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (F(3,24) = 7.445, P = 0.001) and exhibited deficiencies during the EPM (F(3,55) = 4.397, P = 0.008) and PPI (F(3,110) = 5.222, P = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (F(3,16) = 11.906, P < 0.001). These parameters in the sevoflurane-exposed rats that were pretreated with formestane or bumetanide were not different from those in the control rats. Conclusion These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABAAR signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.
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Affiliation(s)
- Jie Wang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China.,Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Baofeng Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.,Department of Anesthesiology and Perioperative Medicine, Affiliated, Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Andrea Allen
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.,The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
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Yu Y, Yang Y, Tan H, Boukhali M, Khatri A, Yu Y, Hua F, Liu L, Li M, Yang G, Dong Y, Zhang Y, Haas W, Xie Z. Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice. Anesthesiology 2020; 133:595-610. [PMID: 32701572 PMCID: PMC7429299 DOI: 10.1097/aln.0000000000003452] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria-adenosine triphosphate (ATP)-Nuak1-Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function. METHODS 6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice. RESULTS Under baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2. CONCLUSIONS Higher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage-dependent cognitive dysfunction after sevoflurane anesthesia.
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Affiliation(s)
- Yang Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Yongyan Yang
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Hong Tan
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Department of Anesthesia, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, P. R. China, 200092
| | - Myriam Boukhali
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Ashok Khatri
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Yonghao Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
| | - Fuzhou Hua
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Department of Anesthesia, Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China, 330006
| | - Ling Liu
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P.R. China, 510120
| | - Mengzhu Li
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China, 200092
| | - Guang Yang
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA, 10032
| | - Yuanlin Dong
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Yiying Zhang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Wilhelm Haas
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
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11
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Li T, Huang Z, Wang X, Zou J, Tan S. Role of the GABAA receptors in the long-term cognitive impairments caused by neonatal sevoflurane exposure. Rev Neurosci 2020; 30:869-879. [PMID: 31145696 DOI: 10.1515/revneuro-2019-0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 03/29/2019] [Indexed: 02/06/2023]
Abstract
Sevoflurane is a widely used inhalational anesthetic in pediatric surgeries, which is considered reasonably safe and reversible upon withdrawal. However, recent preclinical studies suggested that peri-neonatal sevoflurane exposure may cause developmental abnormalities in the brain. The present review aimed to present and discuss the accumulating experimental data regarding the undesirable effects of sevoflurane on brain development as revealed by the laboratory studies. First, we summarized the long-lasting side effects of neonatal sevoflurane exposure on cognitive functions. Subsequently, we presented the structural changes, namely, neuroapoptosis, neurogenesis and synaptogenesis, following sevoflurane exposure in the immature brain. Finally, we also discussed the potential mechanisms underlying subsequent cognitive impairments later in life, which are induced by neonatal sevoflurane exposure and pointed out potential strategies for mitigating sevoflurane-induced long-term cognitive impairments. The type A gamma-amino butyric acid (GABAA) receptor, the main targets of sevoflurane, is excitatory rather than inhibitory in the immature neurons. The excitatory effects of the GABAA receptors have been linked to increased neuroapoptosis, elevated serum corticosterone levels and epigenetic modifications following neonatal sevoflurane exposure in rodents, which might contribute to sevoflurane-induced long-term cognitive abnormalities. We proposed that the excitatory GABAA receptor-mediated HPA axis activity might be a novel mechanism underlying sevoflurane-induced long-term cognitive impairments. More studies are needed to investigate the effectiveness and mechanisms by targeting the excitatory GABAA receptor as a prevention strategy to alleviate cognitive deficits induced by neonatal sevoflurane exposure in future.
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Affiliation(s)
- Tao Li
- Grade 2015 of Clinical Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Zeyi Huang
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Xianwen Wang
- Grade 2015 of Clinical Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Ju Zou
- Department of Parasitology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Sijie Tan
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
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12
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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13
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Li N, Xu N, Lin Y, Lei L, Ju LS, Morey TE, Gravenstein N, Zhang J, Martynyuk AE. Roles of Testosterone and Estradiol in Mediation of Acute Neuroendocrine and Electroencephalographic Effects of Sevoflurane During the Sensitive Period in Rats. Front Endocrinol (Lausanne) 2020; 11:545973. [PMID: 33101193 PMCID: PMC7556268 DOI: 10.3389/fendo.2020.545973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 09/10/2020] [Indexed: 01/14/2023] Open
Abstract
Testosterone (T), predominantly acting through its derivative 17β-estradiol (E2), regulates the brain's sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia's adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane's acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α (Erα) [not estrogen receptor β (Erβ)], Na+-K+-Cl- cotransporter (Nkcc1)/K+-Cl- cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERβ antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABAAR-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.
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Affiliation(s)
- Ningtao Li
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E. Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jiaqiang Zhang, ; Anatoly E. Martynyuk,
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Jiaqiang Zhang, ; Anatoly E. Martynyuk,
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14
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Dias KA, Lawley JS, Gatterer H, Howden EJ, Sarma S, Cornwell WK, Hearon CM, Samels M, Everding B, Liang ASW, Hendrix M, Piper T, Thevis M, Bruick RK, Levine BD. Effect of acute and chronic xenon inhalation on erythropoietin, hematological parameters, and athletic performance. J Appl Physiol (1985) 2019; 127:1503-1510. [DOI: 10.1152/japplphysiol.00289.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This study aimed to assess the efficacy of acute subanesthetic dosages of xenon inhalation to cause erythropoiesis and determine the effect of chronic xenon dosing on hematological parameters and athletic performance. To assess the acute effects, seven subjects breathed three subanesthetic concentrations of xenon: 30% fraction of inspired xenon (FiXe) for 20 min, 50% FiXe for 5 min, and 70% FiXe for 2 min. Erythropoietin (EPO) was measured at baseline, during, and after xenon inhalation. To determine the chronic effects, eight subjects breathed 70% FiXe for 2 min on 7 consecutive days, and EPO, total blood, and plasma volume were measured. Phase II involved assessment of 12 subjects for EPO, total blood volume, maximal oxygen uptake, and 3-km time before and after random assignment to 4 wk of xenon or sham gas inhalation. FiXe 50% and 70% stimulated an increase in EPO at 6 h [+2.3 mIU/mL; 95% confidence interval (CI) 0.1–4.5; P = 0.038] and at 192 h postinhalation (+2.9 mIU/mL; 95% CI 0.6–5.1; P = 0.017), respectively. Seven consecutive days of dosing significantly elevated plasma volume (+491 mL; 95% CI 194–789; P = 0.002). Phase II showed no significant effect on EPO, hemoglobin mass, plasma volume, maximal oxygen uptake, or 3-km time. Acute exposure to subanesthetic doses of xenon caused a consistent increase in EPO, and 7 consecutive days of xenon inhalation significantly expanded plasma volume. However, this physiological response appeared to be transient, and 4 wk of xenon inhalation did not stimulate increases in plasma volume or erythropoiesis, leaving cardiorespiratory fitness and athletic performance unchanged. NEW & NOTEWORTHY This is the first study to examine each element of the cascade by which xenon inhalation is purported to take effect, starting with measurement of the hypoxia-inducible factor effector, erythropoietin, to hemoglobin mass and blood volume and athletic performance. We found that acute exposure to xenon increased serum erythropoietin concentration, although major markers of erythropoiesis remained unchanged. While daily dosing significantly expanded plasma volume, no physiological or performance benefits were apparent following 4 wk of dosing.
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Affiliation(s)
- Katrin A. Dias
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
| | - Justin S. Lawley
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Sports Science, University of Innsbruck, Innsbruck, Austria
| | - Hannes Gatterer
- Department of Sports Science, University of Innsbruck, Innsbruck, Austria
- Institute of Mountain Emergency Medicine, Eurac Research, Bolzano, Italy
| | - Erin J. Howden
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Satyam Sarma
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - Christopher M. Hearon
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mitchel Samels
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
| | - Braden Everding
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
| | | | - Max Hendrix
- University of Texas Southwestern Medical Center, Dallas, Texas
| | - Thomas Piper
- German Sport University Cologne, Institute of Biochemistry/Centre for Preventive Doping Research, Cologne, Germany
| | - Mario Thevis
- German Sport University Cologne, Institute of Biochemistry/Centre for Preventive Doping Research, Cologne, Germany
| | | | - Benjamin D. Levine
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, Dallas, Texas
- University of Texas Southwestern Medical Center, Dallas, Texas
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15
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Yang C, Li C, Sun J, Lu X. Role of estradiol in mediation of etomidate-caused seizure-like activity in neonatal rats. Int J Dev Neurosci 2019; 78:170-177. [PMID: 31202866 DOI: 10.1016/j.ijdevneu.2019.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 05/19/2019] [Accepted: 06/12/2019] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND The goal of this study was to investigate the effect of estradiol in mediation of electroencephalogram (EEG) abnormality induced by etomidate in neonatal rats. METHODS Sprague-Dawley rats were anesthetized using intraperitoneal etomidate for 2 h on postnatal days (P) 4, 5, or 6 and recorded electroencephalogram in two ways. First, pups were recorded EEG two and a half hours under etomidate anesthesia, in subgroups, estradiol receptor antagonist ICI182780 and estradiol synthase inhibitor formestane were given subcutaneously in male rats 15 min prior to etomidate. Second, pups were anesthetized with etomidate for 2 h on P4,5 or 6 and then recovered from anesthesia, EEG were recorded for one hour in two postnatal periods of P9-P11 and P14-P16. Subgroup rats that received bumetanide, NKCC1 inhibitor, to test the NKCC1-GABAAR signaling effect on neonatal brain development, negative control groups and maternally separated for 2 h on P4, 5, or 6 were studied in 16 groups. Each group's n was = 8. RESULTS Male pups showed more severe seizure-like activities than female pups in P4-P6 under etomidate anesthesia. Pups pretreated with ICI182780 and formestane showed a less abnormalities of EEG in male rats. Etomidate caused seizure-like activity in P4-P6 could extend to P9-P11, but not seen in P14-P16, Pretreated with bumetanide only alleviated abnormalities in male pups other than female in P9-P11. CONCLUSIONS Estradiol involves in the NKCC1-GABAAR mediated seizure-like activity caused by etomidte in neonatal rats and these the abnormality lasts near two weeks.
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Affiliation(s)
- Chunyao Yang
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Changsheng Li
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Sun
- Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xihua Lu
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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16
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Ben-Ari Y. Oxytocin and Vasopressin, and the GABA Developmental Shift During Labor and Birth: Friends or Foes? Front Cell Neurosci 2018; 12:254. [PMID: 30186114 PMCID: PMC6110879 DOI: 10.3389/fncel.2018.00254] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 07/24/2018] [Indexed: 12/15/2022] Open
Abstract
Oxytocin (OT) and vasopressin (AVP) are usually associated with sociability and reduced stress for the former and antidiuretic agent associated with severe stress and pathological conditions for the latter. Both OT and AVP play major roles during labor and birth. Recent contradictory studies suggest that they might exert different roles on the GABA excitatory/inhibitory developmental shift. We reported (Tyzio et al., 2006) that at birth, OT exerts a neuro-protective action mediated by an abrupt reduction of intracellular chloride levels ([Cl-]i) that are high in utero, reinforcing GABAergic inhibition and modulating the generation of the first synchronized patterns of cortical networks. This reduction of [Cl-]i levels is abolished in rodent models of Fragile X Syndrome and Autism Spectrum Disorders, and its restoration attenuates the severity of the pathological sequels, stressing the importance of the shift at birth (Tyzio et al., 2014). In contrast, Kaila and co-workers (Spoljaric et al., 2017) reported excitatory GABA actions before and after birth that are modulated by AVP but not by OT, challenging both the developmental shift and the roles of OT. Here, I analyze the differences between these studies and suggest that the ratio AVP/OT like that of excitatory/inhibitory GABA depend on stress and pathological conditions.
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Affiliation(s)
- Yehezkel Ben-Ari
- Neurochlore and Ben-Ari Institute of Neuroarcheology (IBEN), Marseille, France
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17
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Yang J, Ju L, Yang C, Xue J, Setlow B, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Martynyuk AE. Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl - cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats. Neurosci Lett 2018; 685:83-89. [PMID: 30125644 DOI: 10.1016/j.neulet.2018.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/09/2018] [Accepted: 08/16/2018] [Indexed: 01/18/2023]
Abstract
Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl- transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.
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Affiliation(s)
- Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Chunyao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jinhu Xue
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Barry Setlow
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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18
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Ju LS, Yang JJ, Morey TE, Gravenstein N, Seubert CN, Resnick JL, Zhang JQ, Martynyuk AE. Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Br J Anaesth 2018; 121:406-416. [PMID: 30032879 PMCID: PMC6200111 DOI: 10.1016/j.bja.2018.04.034] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 04/03/2018] [Accepted: 05/02/2018] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
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Affiliation(s)
- L-S Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J-J Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - T E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - N Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - C N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J L Resnick
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - J-Q Zhang
- Department of Anesthesiology, Zhengzhou University, Zhengzhou, China
| | - A E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA.
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Makaryus R, Lee H, Robinson J, Enikolopov G, Benveniste H. Noninvasive Tracking of Anesthesia Neurotoxicity in the Developing Rodent Brain. Anesthesiology 2018; 129:118-130. [PMID: 29688900 PMCID: PMC6008207 DOI: 10.1097/aln.0000000000002229] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Potential deleterious effect of multiple anesthesia exposures on the developing brain remains a clinical concern. We hypothesized that multiple neonatal anesthesia exposures are more detrimental to brain maturation than an equivalent single exposure, with more pronounced long-term behavioral consequences. We designed a translational approach using proton magnetic resonance spectroscopy in rodents, noninvasively tracking the neuronal marker N-acetyl-aspartate, in addition to tracking behavioral outcomes. METHODS Trajectories of N-acetyl-aspartate in anesthesia naïve rats (n = 62, postnatal day 5 to 35) were determined using proton magnetic resonance spectroscopy, creating an "N-acetyl-aspartate growth chart." This chart was used to compare the effects of a single 6-h sevoflurane exposure (postnatal day 7) to three 2-h exposures (postnatal days 5, 7, 10). Long-term effects on behavior were separately examined utilizing novel object recognition, open field testing, and Barnes maze tasks. RESULTS Utilizing the N-acetyl-aspartate growth chart, deviations from the normal trajectory were documented in both single and multiple exposure groups, with z-scores (mean ± SD) of -0.80 ± 0.58 (P = 0.003) and -1.87 ± 0.58 (P = 0.002), respectively. Behavioral testing revealed that, in comparison with unexposed and single-exposed, multiple-exposed animals spent the least time with the novel object in novel object recognition (F(2,44) = 4.65, P = 0.015), traveled the least distance in open field testing (F(2,57) = 4.44, P = 0.016), but exhibited no learning deficits in the Barnes maze. CONCLUSIONS Our data demonstrate the feasibility of using the biomarker N-acetyl-aspartate, measured noninvasively using proton magnetic resonance spectroscopy, for longitudinally monitoring anesthesia-induced neurotoxicity. These results also indicate that the neonatal rodent brain is more vulnerable to multiple anesthesia exposures than to a single exposure of the same cumulative duration.
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Affiliation(s)
- Rany Makaryus
- Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY
| | - Hedok Lee
- Department of Anesthesiology, Yale School of Medicine, New Haven, CT
| | - John Robinson
- Department of Psychology, Stony Brook University, Stony Brook, NY
| | - Grigori Enikolopov
- Department of Anesthesiology, Stony Brook Medicine, Stony Brook, NY
- Center for Developmental Genetics, Stony Brook University, Stony Brook, NY
| | - Helene Benveniste
- Department of Anesthesiology, Yale School of Medicine, New Haven, CT
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20
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Yang J, Ju L, Jia M, Zhang H, Sun X, Ji M, Yang J, Martynyuk AE. Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia. Neurosci Lett 2017; 661:137-142. [PMID: 28982596 PMCID: PMC5808428 DOI: 10.1016/j.neulet.2017.09.063] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 09/24/2017] [Accepted: 09/29/2017] [Indexed: 12/16/2022]
Abstract
Several recent studies suggest that in the human population, a routine, short anesthetic in otherwise healthy infants is void of neurodevelopmental insult. On the other hand, many human retrospective epidemiological studies report evidence of cognitive abnormalities in children after testing those who had different anesthesia-requiring procedures in early childhood. We tested in a rat model whether post-anesthesia stressful environmental factors can contribute to developmental abnormalities that were initiated by a relatively short exposure to sevoflurane, the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABAAR) activity. Postnatal day 6 (P6) male Sprague-Dawley rats were anesthetized with sevoflurane for 60min. To simulate subsequent stress, the animals were subjected to a single maternal separation for 180min at P10. To study the role of GABAAR-mediated depolarization, subgroups of P6 rats received a single injection of the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, prior to initiation of anesthesia with sevoflurane. Rats that were exposed to sevoflurane had decreased hypothalamic K+-2Cl- (KCC2) mRNA level (F(2,13)=3.839, P=0.049), increased NKCC1/KCC2 mRNA ratio (F(2,13)=5.043, P=0.024) and increased corticotropin-releasing hormone (CRH) mRNA level (F(2,12)=9.450, P=0.003) at P10, the age at which maternal separation was imposed. Adult rats, neonatally exposed to a combination of sevoflurane and maternal separation, exhibited increases in the escape latencies greater than animals exposed to sevoflurane only (P=0.012), and only rats in the sevoflurane plus maternal separation group spent significantly less time in the target quadrant during the Morris water maze test (F(4,55)=4.856, P=0.002). Bumetanide ameliorated abnormalities induced by sevoflurane and a combination of sevoflurane plus maternal separation. Neonatal exposure to sevoflurane may sensitize to stressors later in life, and post-exposure stress may exacerbate neurodevelopmental abnormalities even after a relatively short exposure to sevoflurane in rodents. The NKCC1 downregulation prior to exposure to the anesthetic may be therapeutic.
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Affiliation(s)
- Jiaojiao Yang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Lingsha Ju
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Min Jia
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Hui Zhang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiaoru Sun
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Muhuo Ji
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jianjun Yang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of FL College of Medicine, Gainesville, FL, United States.
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21
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Ju LS, Yang JJ, Gravenstein N, Seubert CN, Morey TE, Sumners C, Vasilopoulos T, Yang JJ, Martynyuk AE. Role of environmental stressors in determining the developmental outcome of neonatal anesthesia. Psychoneuroendocrinology 2017; 81:96-104. [PMID: 28433802 PMCID: PMC5492971 DOI: 10.1016/j.psyneuen.2017.04.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/28/2017] [Accepted: 04/04/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. METHODS Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl- (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. CONCLUSIONS Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiao-Jiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Colin Sumners
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jian-Jun Yang
- Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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22
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Sun Z, Satomoto M, Adachi YU, Makita K. Apocynin preserves glutamatergic neurons in the basolateral amygdala in mice with neonatal sevoflurane exposure. Korean J Anesthesiol 2017; 70:335-340. [PMID: 28580085 PMCID: PMC5453896 DOI: 10.4097/kjae.2017.70.3.335] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/21/2017] [Accepted: 02/22/2017] [Indexed: 11/26/2022] Open
Abstract
Background Neonatal exposure to anesthetics induces neuronal apoptosis and long-term cognitive dysfunction in rodents. We showed that the nicotinamide adenine dinucleotide phosphate-oxidase inhibitor apocynin not only reduces neurotoxicity by decreasing superoxide levels and preventing mitochondrial dysfunction but also improves long-term memory impairment in neonatal mice exposed to sevoflurane. We also found that after the contextual fear conditioning test, glutamatergic neurons expressed c-Fos (neural activation) regardless of previous exposure to sevoflurane. Moreover, there were fewer c-Fos-expressing glutamatergic neurons in the basolateral amygdala (BLA) after exposure to sevoflurane than after exposure to carrier gas. In this study, we investigated whether the administration of apocynin prior to sevoflurane exposure would preserve glutamatergic neurons in the BLA. Methods Apocynin (50 mg/kg) was injected intraperitoneally into six-day-old male mice 30 min before 6 h of exposure to 3% sevoflurane or carrier gas only. The mice were allowed to mature and then were subjected to the contextual fear conditioning test. The neural activation and neuron population in the BLA were investigated 2 h later. Results Administration of apocynin prior to neonatal sevoflurane exposure not only prevented learning deficits but also preserved c-Fos-expressing glutamatergic neurons in the BLA. Conclusions Apocynin mitigates the cognitive impairment induced by neonatal sevoflurane exposure and preserves c-Fos-expressing glutamatergic neurons in the basolateral amygdala.
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Affiliation(s)
- Zhongliang Sun
- Department of Anesthesiology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Maiko Satomoto
- Department of Anesthesiology, Graduate School of Medicine, Nagoya University, Aichi, Japan
| | - Yushi U Adachi
- Department of Anesthesiology, Graduate School of Medicine, Nagoya University, Aichi, Japan
| | - Koshi Makita
- Department of Anesthesiology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan
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Rosenholm M, Paro E, Antila H, Võikar V, Rantamäki T. Repeated brief isoflurane anesthesia during early postnatal development produces negligible changes on adult behavior in male mice. PLoS One 2017; 12:e0175258. [PMID: 28380075 PMCID: PMC5381906 DOI: 10.1371/journal.pone.0175258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/22/2017] [Indexed: 01/26/2023] Open
Abstract
Brain development is a complex process regulated by genetic programs and activity-dependent neuronal connectivity. Anesthetics profoundly alter neuronal excitability, and anesthesia during early brain development has been consistently associated with neuroapoptosis, altered synaptogenesis, and persistent behavioral abnormalities in experimental animals. However, the depth, and even more the duration and developmental time point(s) of exposure to anesthesia determine the neuropathological and long-term behavioral consequences of anesthetics. Here, we have investigated adulthood phenotypic changes induced by repeated but brief (30 min) isoflurane anesthesia delivered during two distinct developmental periods in male mice. A set of animals were subjected to anesthesia treatments at postnatal days 7, 8 and 9 (P7-9) when the animals are susceptible to anesthesia-induced neuroapoptosis and reduced synaptogenesis. To control the potential influence of (handling) stress, a separate group of animals underwent repeated maternal separations of similar durations. Another set of animals were exposed to the same treatments at postnatal days 15, 16 and 17 (P15-17), a developmental time period when anesthetics have been shown to increase synaptogenesis. Starting from postnatal week 9 the mouse phenotype was evaluated using a battery of behavioral tests that assess general locomotor activity (home cage activity, open field), learning and memory (water maze) and depression- (saccharin preference, forced swim test), anxiety- (light-dark box, stress-induced hyperthermia) and schizophrenia- (nesting, prepulse inhibition) related endophenotypes. Apart from mild impairment in spatial navigation memory, exposure to anesthesia treatments during P7-9 did not bring obvious behavioral alterations in adult animals. Importantly, maternal separation during the same developmental period produced a very similar phenotype during the water maze. Mice exposed to anesthesia during P15-17 showed mild hyperactivity and risk-taking behavior in adulthood, but were otherwise normal. We conclude that significantly longer administration periods are needed in order for early-life repeated exposures to anesthetics to produce behavioral alterations in adult mice.
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Affiliation(s)
- Marko Rosenholm
- Laboratory of Neurotherapeutics, Division of Physiology and Neuroscience, Faculty of Biological and Environmental Sciences, Department of Biosciences, University of Helsinki, Finland
| | - Emmi Paro
- Laboratory of Neurotherapeutics, Division of Physiology and Neuroscience, Faculty of Biological and Environmental Sciences, Department of Biosciences, University of Helsinki, Finland
| | - Hanna Antila
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Vootele Võikar
- Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Tomi Rantamäki
- Laboratory of Neurotherapeutics, Division of Physiology and Neuroscience, Faculty of Biological and Environmental Sciences, Department of Biosciences, University of Helsinki, Finland
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24
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Ji MH, Wang ZY, Sun XR, Tang H, Zhang H, Jia M, Qiu LL, Zhang GF, Peng YG, Yang JJ. Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment. Mol Neurobiol 2016; 54:3759-3770. [DOI: 10.1007/s12035-016-9943-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 05/26/2016] [Indexed: 01/13/2023]
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Repetitive transcranial magnetic stimulation regulates L-type Ca(2+) channel activity inhibited by early sevoflurane exposure. Brain Res 2016; 1646:207-218. [PMID: 27256401 DOI: 10.1016/j.brainres.2016.05.045] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/16/2016] [Accepted: 05/24/2016] [Indexed: 11/21/2022]
Abstract
BACKGROUND Sevoflurane might be harmful to the developing brain. Therefore, it is essential to reverse sevoflurane-induced brain injury. OBJECTIVE This study aimed to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) can regulate L-type Ca(2+) channel activity, which is inhibited by early sevoflurane exposure. METHODS Rats were randomly divided into three groups: control, sevoflurane, and rTMS groups. A Whole-cell patch clamp technique was applied to record L-type Ca(2+) channel currents. The I-V curve, steady-state activation and inactivation curves were studied in rats of each group at different ages (1 week, 2 weeks, 3 weeks, 4 weeks and 5 weeks old). RESULTS In the control group, L-type Ca(2+) channel current density significantly increased from week 2 to week 3. Compared with the control group, L-type Ca(2+) channel currents of rats in the sevoflurane group were significantly inhibited from week 1 to week 3. Activation curves of L-type Ca(2+) channel shifted significantly towards depolarization at week 1 and week 2. Moreover, steady-state inactivation curves shifted towards hyperpolarization from week 1 to week 3. Compared with the sevoflurane group, rTMS significantly increased L-type Ca(2+) channel currents at week 2 and week 3. Activation curves of L-type Ca(2+) channel significantly shifted towards hyperpolarization at week 2. Meanwhile, steady-state inactivation curves significantly shifted towards depolarization at week 2. CONCLUSIONS The period between week 2 and week 3 is critical for the development of L-type Ca(2+) channels. Early sevoflurane exposure inhibits L-type Ca(2+) channel activity and rTMS can regulate L-type Ca(2+) channel activity inhibited by sevoflurane.
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Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats. Neurosci Lett 2016; 618:1-5. [PMID: 26923669 DOI: 10.1016/j.neulet.2016.02.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 02/22/2016] [Accepted: 02/23/2016] [Indexed: 12/20/2022]
Abstract
Animal studies provide strong evidence that general anesthetics (GAs), administered during the early postnatal period, induce long-term cognitive and neurological abnormalities. Because the brain growth spurt in rodents is delayed compared to that in humans, a fundamental question is whether the postnatal human brain is similarly vulnerable. Sevoflurane and propofol, GAs that share positive modulation of the gamma-aminobutyric acid type A receptor (GABAAR) function cause marked increase in corticosterone levels and induce long-term developmental alterations in synaptic activity in rodents. If synaptogenesis is affected, investigation of mechanisms of the synaptic effects of GAs is of high interest because synaptogenesis in humans continues for several years after birth. Here, we compared long-term synaptic effects of etomidate with those of propofol. Etomidate and propofol both positively modulate GABAAR activity, but in contrast to propofol, etomidate inhibits the adrenal synthesis of corticosterone. Postnatal day (P) 4, 5, or 6 rats received five injections of etomidate, propofol, or vehicle control during 5h of maternal separation. Endocrine effects of the anesthetics were evaluated by measuring serum levels of corticosterone immediately after anesthesia or maternal separation. The frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons were measured at P24-40 and P≥80. Only propofol caused a significant increase in serum corticosterone levels (F(4.26)=17.739, P<0.001). In contrast to increased frequency of mIPSCs in the propofol group (F(4.23)=8.731, p<0.001), mIPSC activity in the etomidate group was not different from that in the vehicle groups. The results of this study together with previously published data suggest that anesthetic-caused increase in corticosterone levels is required for GABAergic GAs to induce synaptic effects in the form of a long-term increase in the frequency of hippocampal mIPSCs.
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27
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Zhang J, Xu C, Puentes DL, Seubert CN, Gravenstein N, Martynyuk AE. Role of Steroids in Hyperexcitatory Adverse and Anesthetic Effects of Sevoflurane in Neonatal Rats. Neuroendocrinology 2016; 103:440-51. [PMID: 26159049 PMCID: PMC4698089 DOI: 10.1159/000437267] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 06/28/2015] [Indexed: 11/19/2022]
Abstract
UNLABELLED Recent studies have demonstrated that long-term developmental effects of neonatal anesthesia were more prominent in males. We tested whether steroids, in general, and sex steroids, in particular, are involved in the mediation of sevoflurane-caused paradoxical cortical seizures during the early postnatal period. METHODS Cortical electroencephalograms, hippocampal synaptic activity, serum levels of steroids and the loss of the righting reflex (LORR), a marker of anesthetic effect, were measured on postnatal days 4-6 in Sprague Dawley rats of both genders exposed to 2.1% sevoflurane. RESULTS Episodes of seizures, persistent spikes in electroencephalograms and increases in serum corticosterone were similar in both genders. In the order of increasing potency, the corticosteroid receptor antagonist RU 28318, the estradiol receptor antagonist ICI 182780 and the estradiol synthesis inhibitor formestane decreased sevoflurane-induced seizures. Exogenous estradiol increased sevoflurane-caused seizures, spikes and serum levels of corticosterone. These estradiol-enhanced seizures and spikes were depressed by ICI 182780 and the NKCC1 inhibitor, bumetanide, while RU 28318 decreased seizures only. In hippocampal CA1 neurons, estradiol increased the amplitude, rise time and area under the curve of gamma-aminobutyric acid type A receptor (GABAAR)-mediated miniature postsynaptic currents. Exogenous estradiol shortened, while ICI 182780 and formestane lengthened the time needed for sevoflurane to induce LORR. CONCLUSION These findings provide evidence for gender-independent acute electroencephalographic effects of sevoflurane at this age. Corticosterone and estradiol are involved in the mediation of sevoflurane-induced seizures. Estradiol, but not corticosterone, also contributes to sevoflurane-caused spikes, by enhancing GABAAR-mediated excitation in the cortex. By increasing GABAAR-mediated inhibition in more mature caudal regions of the brain, estradiol contributes to sevoflurane-induced LORR.
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Affiliation(s)
- Jiaqiang Zhang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
- Department of Anesthesiology, People’s Hosptial of Zhengzhou University, Zhengzhou, P.R. China
| | - Changqing Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Dyanet L. Puentes
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Christoph N. Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL
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Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. Neurotox Res 2015; 29:243-55. [PMID: 26678494 DOI: 10.1007/s12640-015-9585-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 11/24/2015] [Accepted: 12/06/2015] [Indexed: 10/24/2022]
Abstract
General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague-Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41-43, and P50-57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.
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Xu C, Tan S, Zhang J, Seubert CN, Gravenstein N, Sumners C, Vasilopoulos T, Martynyuk AE. Anesthesia with sevoflurane in neonatal rats: Developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl(-) importer antagonists. Psychoneuroendocrinology 2015; 60:173-81. [PMID: 26150359 PMCID: PMC4526322 DOI: 10.1016/j.psyneuen.2015.06.016] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 05/22/2015] [Accepted: 06/22/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND 1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities. METHODS Sprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6h; maternally separated and house reared rats served as controls. RESULTS Sevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na(+)-K(+)-2Cl(-) cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity. CONCLUSIONS Sevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities.
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Affiliation(s)
- Changqing Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Sijie Tan
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Jiaqiang Zhang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL,Department of Anesthesiology, People’s Hospital of Zhengzhou University, Zhengzhou, P.R.China
| | - Christoph N. Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL
| | - Colin Sumners
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL,Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL
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Sun Z, Satomoto M, Makita K. Therapeutic effects of intravenous administration of bone marrow stromal cells on sevoflurane-induced neuronal apoptosis and neuroinflammation in neonatal rats. Korean J Anesthesiol 2015; 68:397-401. [PMID: 26257854 PMCID: PMC4524940 DOI: 10.4097/kjae.2015.68.4.397] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 06/04/2014] [Accepted: 06/27/2014] [Indexed: 01/13/2023] Open
Abstract
Background Sevoflurane exposure during the early postnatal period causes neuroinflammation and neuronal apoptosis in rodents. Bone marrow stromal cells (BMSCs) have been shown to protect and repair the damaged central nervous system, for example in ischemic stroke models. In this study, we investigated whether intravenous administration of BMSCs ameliorated neurodegeneration, induced by sevoflurane exposure, in neonatal rats. Methods Sprague-Dawley rat pups (postnatal day 7) were exposed to 2% sevoflurane for 6 h (vehicle group, n = 7). BMSCs were administered 30 min after induction of sevoflurane anesthesia (BMSCs group, n = 7). The pups were exposed to carrier gas only, as a negative control (mock anesthesia group, n = 4). We assessed the therapeutic effects of BMSC treatment by measuring expression of the pro-inflammatory cytokine interleukin-6 (IL-6), and levels of cleaved caspase-3, in brain tissues immediately following sevoflurane anesthesia. Results Analysis of the cleaved caspase-3 bands revealed that levels of activated caspase-3 were elevated in the vehicle group compared with the mock anesthesia group, indicating that a single exposure to sevoflurane at subclinical concentrations can precipitate neuronal apoptosis. BMSC treatment did not suppress apoptosis induced by sevoflurane exposure (compared with the vehicle group). The vehicle group had higher proinflammatory cytokine IL-6 protein levels compared with the mock anesthesia group, indicating that sevoflurane exposure induces IL-6 expression. BMSC treatment suppressed sevoflurane-induced increases in IL-6 expression, indicating that these cells can inhibit the neuroinflammation induced by sevoflurane exposure (vehicle group vs. BMSC group). Conclusions Intravenous administration of BMSCs reduces neuroinflammation, but does not attenuate apoptosis induced by sevoflurane exposure.
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Affiliation(s)
- ZhongLiang Sun
- Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Maiko Satomoto
- Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koshi Makita
- Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Xu KX, Tao J, Zhang N, Wang JZ. Neuroprotective properties of vitamin C on equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in high fat diet fed neonatal mice. Int J Clin Exp Med 2015; 8:10444-58. [PMID: 26379835 PMCID: PMC4565218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/08/2015] [Indexed: 06/05/2023]
Abstract
Obesity has been reported to be one of the significant contributors to various chronic disease conditions. Childhood obesity has been on an alarming increase over recent years leading to various health complications. Millions of children undergo surgery each year as a part of medical care on various health grounds. In the present study, influence of vitamin C on the effect of obesity and over-weight under anaesthetic exposure was analysed. Separate groups of neonatal mice (C57BL/6) were fed on high-fat diet to induce obesity. The mice were administered with vitamin C at 30 and 60 mg/kg b.wt post natal day 1 (P1) to P21. P7 mice were exposed to equipotent doses of isoflurane or sevoflurane or desflurane. Neuroapoptosis was assessed by measuring activated caspase-3 and TUNEL assay. Plasma S100β levels were detected by ELISA. The mice were assessed for their general behaviour. Morris water maze test was performed to assess the spatial working memory. Anesthesia exposure caused severe neuroapoptosis and also raised the levels of plasma S100β. Neuroapotosis, working memory and learning impairments observed following anesthetics were comparatively more profound on high fat diet fed mice. Desflurane exposure resulted in higher apoptotic counts, learning and memory deficits than equipotent dose of isoflurane and sevoflurane. Vitamin C supplementation offered significant protection against anesthetic induced neurotoxicity and behavioural alterations. Vitamin C administration resulted in marked reduction in neurotoxicity induced by anesthesia and as well improved learning and memory of both normal and high fat diet fed mice.
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Affiliation(s)
- Kai-Xiang Xu
- Department of Neurosurgery, 208 Hospital of PLAChangchun 130062, China
| | - Jun Tao
- Department of Spinal Branch, Wendeng Osteopath HospitalWeihai 230038, China
| | - Nan Zhang
- Department of Obstetrics and Gynecology, Renji HospitalShanghai 200127, China
| | - Jian-Zhong Wang
- Department of Neurosurgery, 208 Hospital of PLAChangchun 130062, China
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Chen C, Shen FY, Zhao X, Zhou T, Xu DJ, Wang ZR, Wang YW. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats. ASN Neuro 2015; 7:7/2/1759091415575845. [PMID: 25873307 PMCID: PMC4720175 DOI: 10.1177/1759091415575845] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4–6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.
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Affiliation(s)
- Chong Chen
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China Graduate School, Institute of Science and Technology Austria, Klosterneuburg, Austria
| | - Feng-Yan Shen
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China
| | - Xuan Zhao
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China
| | - Tao Zhou
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China
| | - Dao-Jie Xu
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China
| | - Zhi-Ru Wang
- Institute of Brain Functional Genomics, East China Normal University, Shanghai, China
| | - Ying-Wei Wang
- Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, China
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Propofol-induced electroencephalographic seizures in neonatal rats: the role of corticosteroids and γ-aminobutyric acid type A receptor-mediated excitation. Anesth Analg 2015; 120:433-9. [PMID: 25390279 DOI: 10.1213/ane.0000000000000529] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND An imbalance between excitation and inhibition in the developing central nervous system may result in a pathophysiological outcome. We investigated the mechanistic roles of endocrine activity and γ-aminobutyric acid type A receptor (GABAAR)-mediated excitation in electroencephalographic seizures caused by the GABAAR-selective anesthetic propofol in neonatal rats. METHODS Postnatal day 4-6 Sprague Dawley rats underwent a minor surgical procedure to implant electrodes to measure electroencephalographic activity for 1 hour before and 1 hour after intraperitoneal administration of propofol (40 mg·kg). Various treatments were administered 15 minutes before administration of propofol. RESULTS Episodes of electroencephalographic seizures and persistent low-amplitude spikes occurred during propofol anesthesia. Multifold increases in serum levels of corticosterone (t(10) = -5.062; P = 0.0005) and aldosterone (t(10) = -5.069; P = 0.0005) were detected 1 hour after propofol administration in animals that underwent experimental manipulations identical to those used to study electroencephalographic activity. Pretreatment with bumetanide, the Na-K-2Cl cotransporter inhibitor, which diminishes GABAAR-mediated excitation, eliminated both seizure and spike electroencephalographic activities caused by propofol. Mineralocorticoid and glucocorticoid receptor antagonists, RU 28318 and RU486, depressed electroencephalographic seizures but did not affect the spike electroencephalographic effects of propofol. Etomidate, at a dose sufficient to induce loss of righting reflex, was weak at increasing serum corticosteroid levels and eliciting electroencephalographic seizures. Etomidate given to corticosterone-pretreated rat pups further increased the total duration of electroencephalographic seizures caused by administration of exogenous corticosterone (t(21) = -2.512, P = 0.0203). CONCLUSIONS Propofol increases systemic corticosteroid levels in neonatal rats, which along with GABAAR-mediated excitation appear to be required for propofol-induced neonatal electroencephalographic seizures. Enhancement of GABAAR activity alone may not be sufficient to elicit neonatal electroencephalographic seizures.
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Endocrine and neurobehavioral abnormalities induced by propofol administered to neonatal rats. Anesthesiology 2014; 121:1010-7. [PMID: 24992523 DOI: 10.1097/aln.0000000000000366] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The authors studied whether neonatal propofol anesthesia affects development of the endocrine and neural systems. METHODS Sprague-Dawley rats were anesthetized using intraperitoneal propofol for 5 h on postnatal days (P) 4, 5, or 6. Pups that received either saline or intralipid, but not those in the negative control groups, were also maternally separated for 5 h. Serum levels of corticosterone were measured immediately after anesthesia and in adulthood after prepulse inhibition of acoustic startle testing (≥P80), followed by measurement of hippocampal neuronal activity. RESULTS Propofol acutely increased corticosterone levels to 146.6 ± 23.5 ng/ml (n = 6) versus 16.4 ± 3.5 ng/ml (n = 6) and 18.4 ± 3.2 ng/ml (n = 6) in saline- and intralipd-treated pups, respectively. In adulthood, the propofol group exhibited exacerbated endocrine responses to stress in a form of increased corticosterone levels (1,171.58 ± 149.17 ng/ml [n = 15] vs. 370.02 ± 36.01 ng/ml [n = 10] in the saline group). The propofol group had increased the frequency of miniature inhibitory postsynaptic currents in CA1 neurons of male and female rats, but reduced prepulse inhibition of startle was detected only in males. The Na-K-2Cl cotransporter inhibitor bumetanide, administered to pups before propofol injection, alleviated long-term endocrine and prepulse inhibition abnormalities. Exogenous corticosterone, administered to naive pups, induced synaptic and endocrine but not prepulse inhibition effects, similar to those of propofol. CONCLUSION Propofol-caused acute increases in corticosterone levels and γ-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities.
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Sevoflurane-induced down-regulation of hippocampal oxytocin and arginine vasopressin impairs juvenile social behavioral abilities. J Mol Neurosci 2014; 56:70-7. [PMID: 25417719 PMCID: PMC4382529 DOI: 10.1007/s12031-014-0468-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 11/13/2014] [Indexed: 12/20/2022]
Abstract
Cumulative evidence indicates that early childhood anesthesia can alter a child's future behavioral performance. Animal researchers have found that sevoflurane, the most commonly used anesthetic for children, can produce damage in the neonatal brains of rodents. To further investigate this phenomenon, we focused on the influence of sevoflurane anesthesia on the development of juvenile social behavioral abilities and the pro-social proteins oxytocin (OT) and arginine vasopressin (AVP) in the neonatal hippocampus. A single 6-h sevoflurane exposure for postnatal day 5 mice resulted in decreased OT and AVP messenger RNA (mRNA) and protein levels in the hippocampus. OT and AVP proteins became sparsely distributed in the dorsal hippocampus after the exposure to sevoflurane. Compared with the air-treated group, mice in the sevoflurane-treated group showed signs of impairment in social recognition memory formation and social discrimination ability. Sevoflurane anesthesia reduces OT and AVP activities in the neonatal hippocampus and impairs social recognition memory formation and social discrimination ability in juvenile mice.
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Wise-Faberowski L, Quinonez ZA, Hammer GB. Anesthesia and the developing brain: relevance to the pediatric cardiac surgery. Brain Sci 2014; 4:295-310. [PMID: 24961762 PMCID: PMC4101478 DOI: 10.3390/brainsci4020295] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/02/2014] [Accepted: 04/05/2014] [Indexed: 01/29/2023] Open
Abstract
Anesthetic neurotoxicity has been a hot topic in anesthesia for the past decade. It is of special interest to pediatric anesthesiologists. A subgroup of children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are those children receiving anesthesia for surgical repair of congenital heart disease. These children have a known risk of neurologic deficit after cardiopulmonary bypass for surgical repair of congenital heart disease. Yet, the type of anesthesia used has not been considered as a potential etiology for their neurologic deficits. These children not only receive prolonged anesthetic exposure during surgical repair, but also receive repeated anesthetic exposures during a critical period of brain development. Their propensity to abnormal brain development, as a result of congenital heart disease, may modify their risk of anesthetic neurotoxicity. This review article provides an overview of anesthetic neurotoxicity from the perspective of a pediatric cardiac anesthesiologist and provides insight into basic science and clinical investigations as it relates to this unique group of children who have been studied over several decades for their risk of neurologic injury.
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Affiliation(s)
- Lisa Wise-Faberowski
- Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
| | - Zoel A Quinonez
- Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
| | - Gregory B Hammer
- Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
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Deng J, Lei C, Chen Y, Fang Z, Yang Q, Zhang H, Cai M, Shi L, Dong H, Xiong L. Neuroprotective gases – Fantasy or reality for clinical use? Prog Neurobiol 2014; 115:210-45. [DOI: 10.1016/j.pneurobio.2014.01.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/03/2014] [Accepted: 01/03/2014] [Indexed: 12/17/2022]
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Abstract
BACKGROUND The general anesthetics, isoflurane and sevoflurane, cause developmental abnormalities in neonatal animal models via incompletely understood mechanisms. Despite many common molecular targets, isoflurane and sevoflurane exhibit substantial differences in their actions. The authors sought to determine whether these differences can also be detected at the level of neurodevelopmental effects. METHODS Postnatal rats, 4-6 days old, were exposed to 1.2% isoflurane or 2.1% sevoflurane for 1-6 h and studied for immediate and delayed effects. RESULTS Isoflurane exposure was associated with weaker seizure-like electroencephalogram patterns than sevoflurane exposure. Confronted with a new environment at a juvenile age, the sevoflurane-exposed rats spent significantly more time in an "immobile" state than unexposed rats. Electroencephalographic (mean ± SE, 55.5 ± 12.80 s vs. 14.86 ± 7.03 s; P = 0.014; n = 6-7) and spontaneous behavior (F(2,39) = 4.43; P = 0.018) effects of sevoflurane were significantly diminished by pretreatment with the Na-K-2Cl cotransporter inhibitor bumetanide, whereas those of isoflurane were not. Pretreatment with bumetanide, however, diminished isoflurane-induced activation of caspase-3 in the cerebral cortex (F(2,8) = 22.869; P = 0.002) and prevented impairment in sensorimotor gating function (F(2,36) = 5.978; P = 0.006). CONCLUSIONS These findings in combination with results previously reported by the authors suggest that isoflurane and sevoflurane produce developmental effects acting via similar mechanisms that involve an anesthetic-induced increase in neuronal activity. At the same time, differences in their effects suggest differences in the mediating mechanisms and in their relative safety profile for neonatal anesthesia.
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