The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid -Protein Accumulation

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2007; 27(6):1247-54. DOI: 10.1523/JNEUROSCI.5320-06.2007
Source: PubMed

ABSTRACT The anesthetic isoflurane has been reported to induce apoptosis and increase Abeta generation and aggregation. However, the molecular mechanism underlying these effects remains unknown. We therefore set out to assess whether the effects of isoflurane on apoptosis are linked to amyloid beta-protein (Abeta) generation and aggregation. For this purpose, we assessed the effects of isoflurane on beta-site amyloid beta precursor protein (APP)-cleaving enzyme (BACE) and gamma-secretase, the proteases responsible for Abeta generation. We also tested the effects of inhibitors of Abeta aggregation (iAbeta5, a beta-sheet breaker peptide; clioquinol, a copper-zinc chelator) on the ability of isoflurane to induce apoptosis. All of these studies were performed on naive human H4 neuroglioma cells as well as those overexpressing APP (H4-APP cells). Isoflurane increased the levels of BACE and gamma-secretase and secreted Abeta in the H4-APP cells. Isoflurane-induced Abeta generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Abeta aggregation inhibitors, iAbeta5 and clioquinol, selectively attenuated caspase-3 activation induced by isoflurane. However, isoflurane was able to induce caspase-3 activation in the absence of any detectable alterations of Abeta generation in naive H4 cells. Finally, Abeta potentiated the isoflurane-induced caspase-3 activation in naive H4 cells. Collectively, these findings suggest that isoflurane can induce apoptosis, which, in turn, increases BACE and gamma-secretase levels and Abeta secretion. Isoflurane also promotes Abeta aggregation. Accumulation of aggregated Abeta in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Abeta generation and aggregation, and additional rounds of apoptosis, leading to cell death.

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    • "The dual effects of neuroprotection and neurotoxicity by general volatile anesthetics have been demonstrated by an extensive body of work both in vitro (Zheng and Zuo, 2003; Bickler et al., 2005; Xie et al., 2007; Culley et al., 2011) and in vivo (Culley et al., 2004; Zhao and Zuo, 2004; Kitano et al., 2007; Dong et al., 2009). These complicated results suggest that different parameters such as dose, timing, and exposure duration of volatile anesthetics are critical to the final outcomes and reflect the complexity of volatile anesthetics' effects on the central nervous system. "
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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.
    ASN Neuro 04/2015; 7(2). DOI:10.1177/1759091415575845 · 4.02 Impact Factor
    • "Methods of immobilising arthropods include the use of isoflurane and halothane (Dombrowski et al. 2012; Lewbart 2012). However, chronic exposure to halothane and isoflurane may be harmful to humans (Knill & Gelb 1978; Xie 2007; Lewbart & Mosley 2012). Simpler , less expensive methods of immobilising invertebrates include exposure to CO 2 or cold (Lewbart & Mosley 2012). "
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    New Zealand Entomologist 12/2014; 38(1):1-7. DOI:10.1080/00779962.2014.884533 · 0.87 Impact Factor
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    • "Several groups completed in vitro studies reporting that isoflurane-induced apoptosis and increased amyloid (Ab) protein levels (Xie et al. 2006; Mandal and Fodale 2009; Xie et al. 2007) and that it also increases Ab oligomerization (Eckenhoff et al. 2004). Bianchi et al. (2008) performed one of the first studies in vivo analyzing the brain and behavior changes in Tg2576 amyloid precursor protein (APP) mice and non-transgenic mice exposed to anesthetics. "
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    ABSTRACT: The use of anesthetics and sedatives has been suggested to be a contributor to Alzheimer's disease neuropathogenesis. We wanted to address the in vivo relevance of those substances in the Tg2576 Alzheimer's mouse model. Tg7526 mice were anesthesia-sedated for 90 min once a week for 4 weeks. Y maze, Congo Red, and amyloid beta (Aβ) immunochemistry were performed. We did not find any significant change in the navigation behavior of the exposed mice compared to the controls. Significantly less deposition of Aβ in the CA1 area of the hippocampus and frontal cortex of mice exposed to isoflurane, propofol, diazepam, ketamine, and pentobarbital was observed. In the dentate gyrus, Aβ deposition was significantly greater in the group treated with pentobarbital. Congo Red staining evidenced significantly fewer fibrils in the cortex of mice exposed to diazepam, ketamine, or pentobarbital. The adopted repetitive exposure did not cause a significant detriment in Tg7526 mouse.
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