Isoflurane Differentially Affects Neurogenesis and Long-term Neurocognitive Function in 60-day-old and 7-day-old Rats

Department of Anesthesia and Perioperative Care, University of California, San Francisco 94143, USA.
Anesthesiology (Impact Factor: 5.88). 05/2009; 110(4):834-48. DOI: 10.1097/ALN.0b013e31819c463d
Source: PubMed


Anesthetic agents cause cell death in the developing rodent brain and long-term, mostly hippocampal-dependent, neurocognitive dysfunction. However, a causal link between these findings has not been shown. Postnatal hippocampal neurogenesis affects hippocampal function into adulthood; therefore, the authors tested the hypothesis that isoflurane affects long-term neurocognitive function via an effect on dentate gyrus neurogenesis.
The S-phase marker 5-bromodeoxyuridine was administered at various times before, during, and after 4 h of isoflurane given to postnatal day (P)60 and P7 rats to assess dentate gyrus progenitor proliferation, early neuronal lineage selection, and long-term survival of new granule cell neurons. Fear conditioning and spatial reference memory was tested at various intervals from 2 weeks until 8 months after anesthesia.
In P60 rats, isoflurane increased early neuronal differentiation as assessed by BrdU/NeuroD costaining, decreased progenitor proliferation for 1 day, and subsequently increased progenitor proliferation 5-10 days after anesthesia. In P7 rats, isoflurane did not induce neuronal lineage selection but decreased progenitor proliferation until at least 5 days after anesthesia. Isoflurane improved spatial reference memory of P60 rats long-term, but it caused a delayed-onset, progressive, persistent hippocampal deficit in P7 rats in fear conditioning and spatial reference memory tasks.
The authors conclude that isoflurane differentially affects both neurogenesis and long-term neurocognitive function in P60 and P7 rats. Neurogenesis might mediate the long-term neurocognitive outcome after isoflurane at different ages.

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Available from: Rehan S Alvi, May 08, 2014
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    • "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). In addition, neurogenesis and neurocognitive function of animals at different ages were differentially affected by isoflurane treatment with impairment in P7 rats but improvement in P60 rats (Stratmann et al., 2009). In the context of our experimental conditions, whether and how 1.8% sevoflurane affects hippocampal neurogenesis and learning performance in adult rats awaits further investigation. "
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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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    • "To assess the spatial working memory, Morris water maze test was performed. Our results indicate that isoflurane caused deficits in memory, consistent with previous reports (Satomoto et al., 2009; Stratmann et al., 2009; Kodama et al., 2011). Pterostilbene treatment was able to bring about marked improvements in the performance of the rats in the Morris water maze tests and also improved working memory of the rats. "
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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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    • "In the animal studies, it has been reported that anesthesia may induce neurotoxicity and neurobehavioral deficits in rodents [6-8] and monkeys [9,10] [reviewed in [3]]. A recent study has shown that anesthesia with 3% sevoflurane two hours daily for three, but not one, days induces neuroinflammation and cognitive impairment in young (six day-old) mice [11]. "
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    ABSTRACT: Anesthesia with multiple exposures of commonly used inhalation anesthetic sevoflurane induces neuroinflammation and cognitive impairment in young mice, but anesthesia with a single exposure to sevoflurane does not. AKT/glycogen synthase kinase 3beta (GSK3beta) signaling pathway is involved in neurotoxicity and neurobehavioral deficits. However, whether sevoflurane can induce a dual effect (increase versus decrease) on the activation of AKT/GSK3beta signaling pathway remains to be determined. We therefore set out to assess the effects of sevoflurane on AKT/GSK3beta signaling pathway in vivo and in vitro. Six day-old wild-type mice were exposed to 3% sevoflurane two hours daily for one or three days. In the in vitro studies, H4 human neuroglioma cells were treated with 4% sevoflurane for two or six hours. We then determined the effects of different sevoflurane treatments on the levels of phosphorylated (P)-GSK3beta(ser9) and P-AKT(ser473) by using Western blot analysis. Here we show that anesthesia with 3% sevoflurane two hours daily for one day increased the levels of P-GSK3beta(ser9) and P-AKT(ser473), but the anesthesia with 3% sevoflurane daily for three days decreased them in the mice. The treatment with 4% sevoflurane for two hours increased, but the treatment with 4% sevoflurane for six hours decreased, the levels of P-GSK3beta(ser9) and P-AKT(ser473) in the H4 human neuroglioma cells. Anesthetic sevoflurane might induce a dual effect (increase versus decrease) on the activation of the AKT/GSK3beta signaling pathway. These studies have established a system to perform further studies to determine the effects of sevoflurane on brain function.
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