2016 年 28 巻 3 号 p. 219-231
Propofol is a short-acting intravenous anesthetic agent. Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has a well-known sedative effect. Both agents exhibit cytoprotective effects in the nervous system under ischemic conditions. Recently, the combination of propofol plus dexmedetomidine was used for the sedation of mechanically ventilated patients in an intensive care unit, but there are few experimental reports of the protective effects of the propofol plus dexmedetomidine combination in cells. Meanwhile, intraoperative brain ischemia–reperfusion induces endoplasmic reticulum (ER) stress-mediated apoptosis. The aim of the present study was to clarify molecular details underlying the neuroprotection afforded by the combination of propofol plus dexmedetomidine against thapsigargin (TG)-induced ER stress in human neuroblastoma SH-SY5Y cells, and whether the combination provided more efficient neuroprotection. TG was used to generate ER stress in SH-SY5Y cells. Cells were pretreated with propofol or dexmedetomidine, individually or in combination, for 1 h before cotreatment with TG for 20 h. There was a significant increase in [Ca2+]i, caspase activation, and the expression of ER stress biomarkers in TG-induced apoptotic cells. The increase in [Ca2+]i and the induction of ER stress by TG were suppressed by pretreatment with propofol, dexmedetomidine, and their combination. The dexmedetomidine-induced reduction in caspase activity and ER stress biomarkers was inhibited by pretreatment with an α2-adrenergic receptor antagonist, but was enhanced by pretreatment with a cAMP inhibitor. Treatment with the propofol plus dexmedetomidine combination exhibited the strongest protection against TG-induced apoptosis. These results demonstrate that the combination of propofol plus dexmedetomidine at clinically relevant concentrations suppresses ER stress-induced apoptosis in neuroblastoma SH-SY5Y cells. The findings suggest that the combination of propofol plus dexmedetomidine within a clinically relevant concentration range may be used safely in patients.