• H Wang, Y Dong, J Zhang, Z Xu, G Wang, C A Swain, Y Zhang, and Z Xie.
• Geriatric Anaesthesia Research Unit, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA 02129-2060, USA Department of Anaesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anaesthesiology, Tianjin 300052, PR China.
• Br J Anaesth. 2014 Oct 1;113(4):695-707.

BackgroundIsoflurane has been reported to induce caspase-3 activation, which may induce neurotoxicity and contribute to the pathogenesis of Alzheimer's disease. However, the underlying mechanism is largely unknown, especially whether or not isoflurane can induce ryanodine receptors (RyRs)-associated endoplasmic reticulum (ER) stress, leading to caspase-3 activation. We therefore assessed the effects of isoflurane on RyRs-associated ER stress.MethodsWe treated primary neurones from wild-type (C57BL/6J) mice with 1% and 2% isoflurane for 1, 3, or 6 h. We then measured levels of C/EBP homologous protein (CHOP) and caspase-12, two ER stress markers, using immunocytochemistry staining and western blotting analysis. Dantrolene (5 μM), the antagonist of RyRs, was used to investigate the role of RyRs in the isoflurane-induced ER stress and caspase-3 activation.ResultsIsoflurane 2% for 6 h treatment increased the levels of CHOP (876% vs 100%, P=0.00009) and caspase-12 (276% vs 100%, P=0.006), and induced caspase-3 activation in the neurones. The administration of 2% isoflurane for 3 h (shorter duration), however, only increased the levels of CHOP (309% vs 100%, P=0.003) and caspase-12 (266% vs 100%, P=0.001), without causing caspase-3 activation. The isoflurane-induced ER stress (CHOP: F=16.64, P=0.0022; caspase-12: F=6.13, P=0.0383) and caspase-3 activation (F=32.06, P=0.0005) were attenuated by the dantrolene treatment.ConclusionsThese data imply that isoflurane might induce caspase-3 activation by causing ER stress through RyRs, and dantrolene could attenuate the isoflurane-induced ER stress and caspase-3 activation. Further investigations of the potential neurotoxicity of isoflurane are needed.© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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