title: Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory.
abstract: OBJECTIVE
  There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.
  
  
  METHODS
  We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.
  
  
  RESULTS
  Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5'-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.
  
  
  CONCLUSIONS
  These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation.
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.forename: Hai Ning
authors.initials: HN
authors.lastname: Shi
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Culley
authors.forename: Gregory
authors.initials: G
authors.lastname: Crosby
authors.forename: Edward R
authors.initials: ER
authors.lastname: Marcantonio
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000077335:Desflurane; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007530:Isoflurane / Q000009:adverse effects* / Q000031:analogs & derivatives*; D007858:Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D000077335:Desflurane; D007530:Isoflurane