title: The potential dual effects of anesthetic isoflurane on hypoxia-induced caspase-3 activation and increases in β-site amyloid precursor protein-cleaving enzyme levels.
abstract: BACKGROUND
  β-Amyloid protein (Aβ) accumulation, caspase activation, apoptosis, and hypoxia-induced neurotoxicity have been suggested to be involved in Alzheimer disease neuropathogenesis. Aβ is produced from amyloid precursor protein through proteolytic processing by the aspartyl protease β-site amyloid precursor protein-cleaving enzyme (BACE) and γ-secretase. Inhaled anesthetics have long been considered to protect against neurotoxicity. However, recent studies have suggested that the inhaled anesthetic isoflurane may promote neurotoxicity by inducing caspase activation and apoptosis, and by increasing levels of BACE and Aβ. We therefore sought to determine whether isoflurane can induce concentration-dependent dual effects on hypoxia-induced caspase-3 activation and increases in BACE levels: protection versus promotion.
  
  
  METHODS
  H4 human neuroglioma cells were treated with hypoxia (3% O(2)) alone, different concentrations of isoflurane (0.5% and 2%), and the combination of hypoxia and 0.5% or 2% isoflurane. The levels of caspase-3 cleavage (activation), BACE, and Bcl-2 were determined by Western blot analysis.
  
  
  RESULTS
  We show for the first time that treatment with 0.5% isoflurane for 8 hours attenuated, whereas treatment with 2% isoflurane for 8 hours enhanced, hypoxia-induced caspase-3 activation and increases in BACE levels. The 2% isoflurane treatment also enhanced a hypoxia-induced decrease in Bcl-2 levels.
  
  
  CONCLUSIONS
  These results suggest a potential concept that isoflurane has dual effects (protection versus promotion) on hypoxia-induced toxicity, which may act through Bcl-2 family proteins. These findings could lead to more systematic studies to determine the potential dual effects of anesthetics on Alzheimer disease-associated 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.
authors.forename: Chuxiong
authors.initials: C
authors.lastname: Pan
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Sayre
authors.initials: S
authors.lastname: McAuliffe
authors.forename: Yun
authors.initials: Y
authors.lastname: Yue
authors.forename: Tianzuo
authors.initials: T
authors.lastname: Li
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007530:Isoflurane / Q000009:adverse effects / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018685:Anesthetics, Inhalation; D018696:Neuroprotective Agents; D007530:Isoflurane; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human