Article

Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells

and Department of Anesthesiology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China. ‡ Research Specialist, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. § Research Visiting Scholar, Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Anesthesiology (Impact Factor: 5.88). 01/2013; 118(3). DOI: 10.1097/ALN.0b013e3182833fae
Source: PubMed

ABSTRACT

Background:
Previous studies have demonstrated that isoflurane can provide both neuroprotection and neurotoxicity in various tissue culture models and in rodent developing brains. The cellular and molecular mechanisms mediating these dual effects are not clear, but the exposure level and duration of isoflurane appear to be determinant factors.

Methods:
Using the ReNcell CX (Millipore, Billerica, MA) human neural progenitor cell line, the authors investigated the impact of prolonged exposure to varying isoflurane concentrations on cell survival and neurogenesis. In addition, the authors assessed the impact of short isoflurane preconditioning on elevation of cytosolic Ca concentration and cytotoxic effects mediated by prolonged isoflurane exposures and the contribution of inositol-1,4,5-trisphosphate or ryanodine receptor activation to these processes.

Results:
Short exposures to low isoflurane concentrations promote proliferation and differentiation of ReNcell CX cells, with no cell damage. However, prolonged exposures to high isoflurane concentrations induced significant ReNcell CX cell damage and inhibited cell proliferation. These prolonged exposures suppressed neuronal cell fate and promoted glial cell fate. Preconditioning of ReNcell CX cultures with short exposures to low concentrations of isoflurane ameliorated the effects of prolonged exposures to isoflurane. Pretreatment of ReNcell cultures with inositol-1,4,5-trisphosphate or ryanodine receptor antagonists mostly prevented isoflurane-mediated effects on survival, proliferation, and differentiation. Finally, isoflurane-preconditioned cultures showed significantly less isoflurane-evoked changes in calcium concentration.

Conclusion:
The commonly used general anesthetic isoflurane exerts dual effects on neuronal stem cell survival, proliferation, and differentiation, which may be attributed to differential regulation of calcium release through activation of endoplasmic reticulum localized inositol-1,4,5-trisphosphate and/or ryanodine receptors.

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    • "//blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/ASNJ/Vol00000/150009/APPFile/SG-ASNJ150009.3d (ASN) [PREPRINTER stage] exposure to high isoflurane concentrations induced cell damage and inhibited proliferation (Zhao et al., 2013). "
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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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    • "Stem-cellderived models with their capacity to proliferate and differentiate provide advantages for detecting potential anesthetic-induced neurotoxicity and underlying mechanisms (Figure 2). These systems provide reliable and simple in vitro models, that can within a short time frame provide data for evaluating the potential adverse effects of developmental anesthetic exposures and associated cellular mechanisms [56]. The use of neural stem cell models, especially those of human origin, holds promise for helping to elucidate relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to the general anesthetics. "

    Full-text · Article · Jan 2015
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    • "Besides diazoxide, several chemical compounds have also been demonstrated to be effective in preconditioning SCs by improving their survival, proliferation, and differentiation either in vitro or after transplantation in pre-clinical models (Table  2) [99-108]. Since the mechanisms of action of these drugs are different from those attributable to the hypoxic treatments, they will be not discussed further. "
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    ABSTRACT: The efficiency of regenerative medicine can be ameliorated by improving the biological performances of stem cells before their transplantation. Several ex-vivo protocols of non-damaging cell hypoxia have been demonstrated to significantly increase survival, proliferation and post-engraftment differentiation potential of stem cells. The best results for priming cultured stem cells against a following, otherwise lethal, ischemic stress have been obtained with brief intermittent episodes of hypoxia, or anoxia, and reoxygenation in accordance with the extraordinary protection afforded by the conventional maneuver of ischemic preconditioning in severely ischemic organs. These protocols of hypoxic preconditioning can be rather easily reproduced in a laboratory; however, more suitable pharmacological interventions inducing stem cell responses similar to those activated in hypoxia are considered among the most promising solutions for future applications in cell therapy. Here we want to offer an up-to-date review of the molecular mechanisms translating hypoxia into beneficial events for regenerative medicine. To this aim the involvement of epigenetic modifications, microRNAs, and oxidative stress, mainly activated by hypoxia inducible factors, will be discussed. Stem cell adaptation to their natural hypoxic microenvironments (niche) in healthy and neoplastic tissues will be also considered.
    Full-text · Article · Aug 2013 · Journal of Biomedical Science
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