| Description |
Author Affiliation: Wang H ( 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 Res); Dong Y ( 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.); Zhang J ( 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, Tongji Hospital, Tongji Medical College, Huazhong Univer); Xu Z ( 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.); Wang G ( Department of Anaesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anaesthesiology, Tianjin 300052, PR China.); Swain CA ( 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.); Zhang Y ( 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.); Xie Z ( 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 zxie@partners.org.) |
| Abstract |
BACKGROUND: Isoflurane 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. METHODS: We 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. RESULTS: Isoflurane 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. CONCLUSIONS: These 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. |
