title: Hydrogen-rich saline attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels.
abstract: OBJECTIVE
  The inhaled general anesthetic isoflurane has been shown to induce caspase-3 activation in vitro and in vivo. The underlying mechanisms and functional consequences of this activity remain unclear. Isoflurane can induce caspase-3 activation by causing accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and reduction in adenosine triphosphate (ATP) levels. This study aimed to investigate the protective effect of hydrogen, a novel antioxidant, against isoflurane-induced caspase-3 activation and cognitive impairment.
  
  
  METHODS
  H4 human neuroglioma cells overexpressing human amyloid precursor protein were treated with saline or hydrogen-rich saline (HS, 300 μM), with or without 2% isoflurane, for 6 h or 3 h. Western blot analysis, fluorescence assays, and a mitochondrial swelling assay were used to evaluate caspase-3 activation, levels of ROS and ATP, and mitochondrial function. The effect of the interaction of isoflurane (1.4% for 2 h) and HS (5 mL/kg) on cognitive function in mice was also evaluated using a fear conditioning test.
  
  
  RESULTS
  We found that HS attenuated isoflurane-induced caspase-3 activation. Moreover, HS treatment mitigated isoflurane-induced ROS accumulation, opening of mitochondrial permeability transition pores, reduction in mitochondrial membrane potential, and reduction in cellular ATP levels. Finally, HS significantly alleviated isoflurane-induced cognitive impairment in mice.
  
  
  CONCLUSIONS
  Our results suggest that HS attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings warrant further research into the underlying mechanisms of this activity, and indicate that HS has the potential to attenuate anesthesia neurotoxicity.
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Lengchen
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Fuqing
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Mengzhu
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Niu
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Shukun
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai, 200072, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Zheng
keywords: Hydrogen; caspase-3; cognitive impairment; isoflurane