H Wang1, Y Dong2, J Zhang3, Z Xu2, G Wang4, C A Swain2, Y Zhang2, Z Xie5. 1. 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. 2. 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. 3. 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 University of Science and Technology, Wuhan 430030, PR China. 4. Department of Anaesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anaesthesiology, Tianjin 300052, PR China. 5. 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.
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.
Authors: Ansgar M Brambrink; Alex S Evers; Michael S Avidan; Nuri B Farber; Derek J Smith; Xuezhao Zhang; Gregory A Dissen; Catherine E Creeley; John W Olney Journal: Anesthesiology Date: 2010-04 Impact factor: 7.892
Authors: Niccolò Terrando; Marek Brzezinski; Vincent Degos; Lars I Eriksson; Joel H Kramer; Jacqueline M Leung; Bruce L Miller; William W Seeley; Susana Vacas; Michael W Weiner; Kristine Yaffe; William L Young; Zhongcong Xie; Mervyn Maze Journal: Mayo Clin Proc Date: 2011-09 Impact factor: 7.616
Authors: Miguel A Burguillos; Tomas Deierborg; Edel Kavanagh; Annette Persson; Nabil Hajji; Albert Garcia-Quintanilla; Josefina Cano; Patrik Brundin; Elisabet Englund; Jose L Venero; Bertrand Joseph Journal: Nature Date: 2011-03-09 Impact factor: 49.962
Authors: Zhongcong Xie; Deborah J Culley; Yuanlin Dong; Guohua Zhang; Bin Zhang; Robert D Moir; Matthew P Frosch; Gregory Crosby; Rudolph E Tanzi Journal: Ann Neurol Date: 2008-12 Impact factor: 10.422
Authors: Hyo-Seok Na; Nicole L Brockway; Katherine R Gentry; Elyce Opheim; Margaret M Sedensky; Philip G Morgan Journal: Neurotoxicol Teratol Date: 2016-10-29 Impact factor: 3.763
Authors: Sara M Zarate; Gauri Pandey; Sunanda Chilukuri; Jose A Garcia; Brittany Cude; Shannon Storey; Nihal A Salem; Eric A Bancroft; Michelle Hook; Rahul Srinivasan Journal: J Neurochem Date: 2021-01-10 Impact factor: 5.372