title: Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment.
abstract: Anesthetic isoflurane has been reported to induce caspase-3 activation. The underlying mechanism(s) and targeted intervention(s), however, remain largely to be determined. Vitamin C (VitC) inhibits oxidative stress and apoptosis. We therefore employed VitC to further determine the up-stream mechanisms and the down-stream consequences of the isoflurane-induced caspase-3 activation. H4 human neuroglioma cells overexpressed human amyloid precursor protein (H4-APP cells) and rat neuroblastoma cells were treated either with (1) 2% isoflurane or (2) with the control condition, plus saline or 400 μM VitC for 3 or 6 h. Western blot analysis and fluorescence assay were utilized at the end of the experiments to determine caspase-3 activation, levels of reactive oxygen species and ATP, and mitochondrial function. The interaction of isoflurane (1.4% for 2 h) and VitC (100 mg/kg) on cognitive function in mice was also assessed in the fear conditioning system. Here, we show for the first time that the VitC treatment attenuated the isoflurane-induced caspase-3 activation. Moreover, VitC mitigated the isoflurane-induced increases in the levels of reactive oxygen species, opening of mitochondrial permeability transition pore, reduction in mitochondrial membrane potential, and the reduction in ATP levels in the cells. Finally, VitC ameliorated the isoflurane-induced cognitive impairment in the mice. Pending confirmation from future studies, these results suggested that VitC attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings would promote further research into the underlying mechanisms and targeted interventions of anesthesia neurotoxicity.
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129-2060, USA.|Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, College of Life Science, Jilin University, Changchun, People's Republic of China.
authors.forename: Baiqi
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129-2060, USA.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129-2060, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Wang
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129-2060, USA.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA, 02129-2060, USA. zxie@mgh.harvard.edu.
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D007530:Isoflurane; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001205:Ascorbic Acid
keywords: Caspase-3; Cognitive function; Isoflurane; Vitamin C