Comparison of the Neuroapoptotic Properties of Equipotent Anesthetic Concentrations of Desflurane, Isoflurane, or Sevoflurane in Neonatal Mice

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Anesthesiology (Impact Factor: 5.88). 03/2011; 114(3):578-87. DOI: 10.1097/ALN.0b013e3182084a70
Source: PubMed


Volatile anesthetics facilitate surgical procedures and imaging studies in millions of children every year. Neuronal cell death after prolonged exposure to isoflurane in developing animals has raised serious concerns regarding its safe use in children. Although sevoflurane and desflurane are becoming more popular for pediatric anesthesia, their cytotoxic effects have not been compared with those of isoflurane. Accordingly, using newborn mice, the current study established the respective potencies of desflurane, isoflurane, and sevoflurane and then compared equipotent doses of these anesthetics regarding their effects on cortical neuroapoptosis.
Minimum alveolar concentrations were determined in littermates (aged 7-8 days, n = 42) using tail-clamp stimulation in a bracketing study design. By using equipotent doses of approximately 0.6 minimum alveolar concentration, another group of littermates was randomly assigned to receive desflurane, isoflurane, or sevoflurane or to fast in room air for 6 h. After exposure, animals (n = 47) were euthanized, neocortical apoptotic neuronal cell death was quantified, and caspase 3 activity was compared between the four groups.
The minimum alveolar concentration was determined to be 12.2% for desflurane, 2.7% for isoflurane, and 5.4% for sevoflurane. After a 6-h exposure to approximately 0.6 minimum alveolar concentration of desflurane, isoflurane, or sevoflurane, neuronal cell death and apoptotic activity were significantly increased, irrespective of the specific anesthetic used.
In neonatal mice, equipotent doses of the three commonly used inhaled anesthetics demonstrated similar neurotoxic profiles, suggesting that developmental neurotoxicity is a common feature of all three drugs and cannot be avoided by switching to newer agents.

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    • "(ASN) [PREPRINTER stage] 1.8% sevoflurane may involve influences on the function of other brain regions, such as neurogenesis in subventricular zone (SVZ), or even some potential neurotoxic effects. For example, one study has indicated that a 6- hour exposure to approximately 0.6 minimum alveolar concentration of sevoflurane increased neocortical cell death and apoptosis in neonatal mice (Istaphanous et al., 2011). Compared with adult or aged animals, neonates have been shown to be more sensitive to sevoflurane treatment (Callaway et al., 2012; Cao et al., 2012; Fang et al., 2012; Shih et al., 2012). "
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    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. © The Author(s) 2015.
    Full-text · Article · Apr 2015 · ASN Neuro
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    • "Cleaved caspase-3 expression was used as marker of apoptosis and cell death. Caspase-3 has been previously validated to be an indicator of apoptosis in anesthesia induced neuroapoptosis (Jevtovic-Todorovic et al., 2003; Rizzi et al., 2008; Istaphanous et al., 2011; Kong et al., 2011). The elevated caspase-3 expressions following isoflurane exposure is indicative of apoptosis. "
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    ABSTRACT: Increasing numbers of children undergo surgery and are exposed to anesthesia that raises concerns regarding the safety of frequently employed anesthetics. Isoflurane, often used in pediatric anesthesia, has been reported to cause neurodegeneration in animal models. The study investigates the effectiveness of pterostilbene on neurodegeneration caused by isoflurane. Separate groups of neonatal mice were administered with pterostilbene at 10, 20 or 40 mg/kg from post natal day 1 (P1) to P15. On P7, rats received isoflurane at 0.75% for 6 hours. Control rats received no anesthesia or pterostilbene. Neuroapoptosis following isoflurane exposure were markedly reduced by pterostilbene, further pterostilbene down-regulated the expressions of caspase-3, Bad, phospho-JNK and phospho-c-Jun and as well improved the expressions of Bcl-xL, JNK, phospho-Bad and phospho-Akt. Pterostilbene enhanced the performance of rats in Morris water maze tests. The observations suggest that pterostilbene was able to effectively reduce isoflurane-induced neurodegeneration. © 2015, Bangladesh Pharmacological Society. All right reserved.
    Preview · Article · Mar 2015 · Bangladesh Journal of Pharmacology
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    • "The effects associated with desflurane, though, are less well described. Similar to other volatile anesthetics, desflurane in neonates has been shown to induce cell death [37], [38]. However, few studies of behavior have been performed, and only one of these has demonstrated cognitive impairment [38]. "
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    ABSTRACT: Background Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue. Methods Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition. Results Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory. Conclusion Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane.
    Full-text · Article · Aug 2014 · PLoS ONE
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