title: Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain.
abstract: OBJECTIVE
  Previously we reported that exposure of 6-day-old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust neuroapoptosis response in developing brain. We have also observed (unpublished data) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane.
  
  
  METHODS
  Neonatal (P6) rhesus macaques were exposed for 5 hours to isoflurane anesthesia according to current clinical standards in pediatric anesthesia. Brains were collected 3 hours later and examined immunohistochemically to analyze apoptotic neuronal and glial death.
  
  
  RESULTS
  Brains exposed to isoflurane displayed significant apoptosis in both the white and gray matter throughout the central nervous system. Approximately 52% of the dying cells were glia, and 48% were neurons. Oligodendrocytes (OLs) engaged in myelinogenesis were selectively vulnerable, in contrast to OL progenitors, astrocytes, microglia, and interstitial neurons. When adjusted for control rates of OL apoptosis, the percentage of OLs that degenerated in the forebrain white matter of the isoflurane-treated group was 6.3% of the total population of myelinating OLs.
  
  
  CONCLUSIONS
  Exposure of the infant rhesus macaque brain to isoflurane for 5 hours is sufficient to cause widespread apoptosis of neurons and OLs throughout the developing brain. Deletion of OLs at a stage when they are just beginning to myelinate axons could potentially have adverse long-term neurobehavioral consequences that might be additive to the potential consequences of isoflurane-induced neuroapoptosis.
authors.affiliation: Departments of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239-3098, USA. brambrin@ohsu.edu
authors.forename: Ansgar M
authors.initials: AM
authors.lastname: Brambrink
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Back
authors.forename: Art
authors.initials: A
authors.lastname: Riddle
authors.forename: Xi
authors.initials: X
authors.lastname: Gong
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Moravec
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dissen
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Creeley
authors.forename: Krikor T
authors.initials: KT
authors.lastname: Dikranian
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology*; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D007150:Immunohistochemistry; D007530:Isoflurane / Q000633:toxicity*; D008253:Macaca mulatta; D009186:Myelin Sheath / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects*; D016707:Tissue Fixation
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane; D020169:Caspases