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

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 human neural progenitor cell line, we investigated the impact of prolonged exposure to varying isoflurane concentrations on cell survival and neurogenesis. In addition, we assessed the impact of short isoflurane preconditioning on elevation of cytosolic Ca2+ concentration and cytotoxic effects mediated by prolonged isoflurane exposures and the contribution of InsP3 or ryanodine receptors 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, while promoting 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 InsP3 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 InsP3 and/or ryanodine receptors.

P1‐081: Chronic Treatment With Anesthetic Propofol Attenuates B‐amyloid Protein Levels in Brain Tissues of Aged Mice

“…Some anesthetics, e.g., isoflurane, have been shown to induce neurotoxicity and neurobehavioral deficits in vitro and in vivo [25,[33][34][35][36][37][38][39][40][41][42][43][44][45][46]. Therefore, the current findings that propofol attenuated Aβ levels in brain tissues of mice suggested that more studies are needed to assess whether propofol could be a better choice when providing anesthesia care for AD patients or senior patients who are vulnerable to develop postoperative cognitive dysfunction.…”

Neuroprotective effects of pterostilbene against isoflurane-induced apoptosis through regulating the JNK and PI3K/Akt pathway in neonatal rats

“…Isoflurane has been demonstrated to act via activation of inositol-1,4,5-trisphosphate (IP3) receptors and also cause change in intracellular calcium homeostasis Yang et al, 2008;Zhao et al, 2013). Isoflurane causes intense calcium release from the endoplasmic reticulum than sevoflurane or desflurane Yang et al, 2008).…”

MicroRNAs: New Players in Anesthetic-Induced Developmental Neurotoxicity

“…Development of an in vitro neurogenesis system using human stem cells has opened up avenues of research for advancing our understanding of human brain development and the issues relevant to anesthetic-induced developmental toxicity in human neuronal lineages under controlled conditions. Recent studies from our and other groups, showed that isoflurane influenced human NSC proliferation and neurogenesis [47] and ketamine dose- and time-dependently induced hESC-derived neuron death [43]. Additionally, when cells underwent different lengths of exposure to propofol and were subjected to single and multiple exposures, propofol induced cell death in the hESC-derived neurons in a time, dose, and exposure number-dependent manner [45].…”