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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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Ju LS, Morey TE, Seubert CN, Martynyuk AE. Intergenerational Perioperative Neurocognitive Disorder. BIOLOGY 2023; 12:biology12040567. [PMID: 37106766 PMCID: PMC10135810 DOI: 10.3390/biology12040567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023]
Abstract
Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Timothy E Morey
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Christoph N Seubert
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Anatoly E Martynyuk
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
- Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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3
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Fu N, Wang Y, Zhu R, Li N, Zeng S, Miao M, Yang Y, Sun M, Zhang J. Bicuculline and Bumetanide Attenuate Sevoflurane-Induced Impairment of Myelination and Cognition in Young Mice. ACS Chem Neurosci 2023; 14:1146-1155. [PMID: 36802490 DOI: 10.1021/acschemneuro.2c00764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023] Open
Abstract
Sevoflurane (Sevo) is one of the most commonly used general anesthetics for infants and young children. We investigated whether Sevo impairs neurological functions, myelination, and cognition via the γ-aminobutyric acid A receptor (GABAAR) and Na+-K+-2Cl- cotransporter (NKCC1) in neonatal mice. On postnatal days 5-7, mice were exposed to 3% Sevo for 2 h. On postnatal day 14, mouse brains were dissected, and oligodendrocyte precursor cell line level lentivirus knockdown of GABRB3, immunofluorescence, and transwell migration assays were performed. Finally, behavioral tests were conducted. Multiple Sevo exposure groups exhibited increased neuronal apoptosis levels and decreased neurofilament protein levels in the mouse cortex compared with the control group. Sevo exposure inhibited the proliferation, differentiation, and migration of the oligodendrocyte precursor cells, thereby affecting their maturation process. Electron microscopy revealed that Sevo exposure reduced myelin sheath thickness. The behavioral tests showed that multiple Sevo exposures induced cognitive impairment. GABAAR and NKCC1 inhibition provided protection against Sevo-induced neurotoxicity and cognitive dysfunction. Thus, bicuculline and bumetanide can protect against Sevo-induced neuronal injury, myelination impairment, and cognitive dysfunction in neonatal mice. Furthermore, GABAAR and NKCC1 may be mediators of Sevo-induced myelination impairment and cognitive dysfunction.
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Affiliation(s)
- Ningning Fu
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.,Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yangyang Wang
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Ruilou Zhu
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Ningning Li
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.,Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Shuang Zeng
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.,Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Mengrong Miao
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Yitian Yang
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Mingyang Sun
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
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Yang Z, Tong Y, Brant JO, Li N, Ju LS, Morey TE, Gravenstein N, Setlow B, Zhang J, Martynyuk AE. Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats. Anesth Analg 2022; 135:877-887. [PMID: 35759382 PMCID: PMC9481710 DOI: 10.1213/ane.0000000000006125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.
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Affiliation(s)
- Zhengbo Yang
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Yuanyuan Tong
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | | | - Ningtao Li
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Timothy E 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
- McKnight Brain Institute
| | - Barry Setlow
- Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida
| | - Jiaqiang Zhang
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute
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Fu N, Zhu R, Zeng S, Li N, Zhang J. Effect of Anesthesia on Oligodendrocyte Development in the Brain. Front Syst Neurosci 2022; 16:848362. [PMID: 35664684 PMCID: PMC9158484 DOI: 10.3389/fnsys.2022.848362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/28/2022] [Indexed: 11/13/2022] Open
Abstract
Oligodendrocytes (OLs) participate in the formation of myelin, promoting the propagation of action potentials, and disruption of their proliferation and differentiation leads to central nervous system (CNS) damage. As surgical techniques have advanced, there is an increasing number of children who undergo multiple procedures early in life, and recent experiments have demonstrated effects on brain development after a single or multiple anesthetics. An increasing number of clinical studies showing the effects of anesthetic drugs on the development of the nervous system may mainly reside in the connections between neurons, where myelin development will receive more research attention. In this article, we review the relationship between anesthesia exposure and the brain and OLs, provide new insights into the development of the relationship between anesthesia exposure and OLs, and provide a theoretical basis for clinical prevention of neurodevelopmental risks of general anesthesia drugs.
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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 DOI: 10.1093/biolre/ioab129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [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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7
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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: 85] [Impact Index Per Article: 17.0] [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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9
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Lin Y, Lei L, Ju LS, Xu N, Morey TE, Gravenstein N, Yang J, Martynyuk AE. Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms. Neurosci Lett 2020; 735:135240. [PMID: 32650051 DOI: 10.1016/j.neulet.2020.135240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/09/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K+-2Cl- (Kcc2) Cl- exporter expression, which regulates developmental maturation of GABA type A receptor (GABAAR) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. METHODS Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. RESULTS Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. CONCLUSIONS Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.
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Affiliation(s)
- Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - 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
| | - Ning Xu
- 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; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jianjun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - 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.
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10
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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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11
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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: 7] [Impact Index Per Article: 1.4] [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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12
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Abstract
BACKGROUND Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. METHODS Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. RESULTS Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). CONCLUSIONS Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.
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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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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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15
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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 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] [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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16
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Martynyuk AE, Yang JJ, Zhang JQ. Neurodevelopmental effects of anesthesia and environmental factors. Oncotarget 2017; 8:9009-9010. [PMID: 28107183 PMCID: PMC5354707 DOI: 10.18632/oncotarget.14694] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Jian-Jun Yang
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Jia-Qiang Zhang
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
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