title: The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.
abstract: OBJECTIVE
  An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.
  
  
  METHODS
  We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.
  
  
  CONCLUSIONS
  Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. zxie@partners.org
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Culley
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Gregory
authors.initials: G
authors.lastname: Crosby
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D016229:Amyloid beta-Peptides / Q000032:analysis / Q000096:biosynthesis*; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D007530:Isoflurane; D020169:Caspases