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      Sevoflurane anesthesia during pregnancy in mice induces hearing impairment in the offspring

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          Abstract

          Introduction

          Exposure to gamma-aminobutyric acid-mimetics and N-methyl-D-aspartate-receptor antagonists during pregnancy may lead to hearing loss and long-term behavioral abnormalities in the offspring. The purpose of this study was to explore the association between prenatal exposure to sevoflurane (SEV) anesthesia and hearing impairment in mice.

          Materials and methods

          On gestational day 15, pregnant Kunming mice were exposed for 2 hours to 2.5% SEV plus 100% oxygen (anesthesia group) or 100% oxygen alone (control group).

          Results

          During auditory brainstem response testing on P30, offspring of the anesthesia group mice exhibited higher hearing thresholds at 8, 16, 24, and 32 kHz; longer peak latency of wave II at all four frequencies; and longer interpeak latencies from waves II to V at 16, 24, and 32 kHz, compared to the control offspring. Caspase-3, iNOS, and COX-2 activation occurred in the fetal cochlea of the anesthesia group. Mitochondrial swelling was observed in the anesthesia group offspring at P1 and P15.

          Conclusion

          Our results suggest that SEV exposure during pregnancy may cause detrimental effects on the developing auditory system.

          Most cited references30

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          Early exposure to anesthesia and learning disabilities in a population-based birth cohort.

          Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. The authors studied association between anesthetic exposure before age 4 yr and the development of reading, written language, and math learning disabilities (LD). This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota, from 1976 to 1982 and who remained in the community at 5 yr of age were reviewed to identify children with LD. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of LD, adjusting for gestational age at birth, sex, and birth weight. Of the 5,357 children in this cohort, 593 received general anesthesia before age 4 yr. Compared with those not receiving anesthesia (n = 4,764), a single exposure to anesthesia (n = 449) was not associated with an increased risk of LD (hazard ratio = 1.0; 95% confidence interval, 0.79-1.27). However, children receiving two anesthetics (n = 100) or three or more anesthetics (n = 44) were at increased risk for LD (hazard ratio = 1.59; 95% confidence interval, 1.06-2.37, and hazard ratio = 2.60; 95% confidence interval, 1.60-4.24, respectively). The risk for LD increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable) (P = 0.016). Exposure to anesthesia was a significant risk factor for the later development of LD in children receiving multiple, but not single anesthetics. These data cannot reveal whether anesthesia itself may contribute to LD or whether the need for anesthesia is a marker for other unidentified factors that contribute to LD.
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            Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits.

            During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood. Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests--spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)--were conducted on mice aged 55-70 days. Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol. This study shows that both a gamma-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-D-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.
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              Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory.

              There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined. We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test. Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5'-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species. These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation. Copyright © 2012 American Neurological Association.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                22 June 2018
                : 12
                : 1827-1836
                Affiliations
                [1 ]Department of Anesthesiology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai 200031, People’s Republic of China
                [2 ]Research Center, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai 200031, People’s Republic of China
                [3 ]Department of Otorhinolaryngology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai 200031, People’s Republic of China
                Author notes
                Correspondence: Huiqian Yu, Department of Otorhinolaryngology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, People’s Republic of China, Tel +86 21 6437 7134, Fax +86 21 6437 3416, Email yhq925@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-1827
                10.2147/DDDT.S156040
                6020999
                b5908c42-0589-4bf5-be90-700e9bc429ee
                © 2018 Shen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                sevoflurane,auditory brainstem response,apoptosis,cochlea,pregnant mice

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