title: Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions.
abstract: BACKGROUND
  General anaesthesia facilitates surgical operations and painful interventions in millions of patients every year. Recent observations of anaesthetic-induced neuronal cell death in newborn animals have raised substantial concerns for young children undergoing anaesthesia. However, it remains unclear why some brain regions are more affected than others, why certain neurones are eliminated while neighbouring cells are seemingly unaffected, and what renders the developing brain exquisitely vulnerable, while the adult brain apparently remains resistant to the phenomenon.
  
  
  METHODS
  Neonatal (P7), juvenile (P21), and young adult mice (P49) were anaesthetized with 1.5% isoflurane. At the conclusion of anaesthesia, activated cleaved caspase 3 (AC3), a marker of apoptotic cell death, was quantified in the neocortex (RSA), caudoputamen (CPu), hippocampal CA1 and dentate gyrus (DG), cerebellum (Cb), and olfactory bulb (GrO) and compared with that found in unanaesthetized littermates.
  
  
  RESULTS
  After anaesthetic exposure, increased AC3 was detected in neonatal mice in RSA (11-fold, compared with controls), CPu (10-fold), CA1 (three-fold), Cb (four-fold), and GrO (four-fold). Surprisingly, AC3 continued to be elevated in the DG and GrO of juvenile (15- and 12-fold, respectively) and young adult mice (two- and four-fold, respectively).
  
  
  CONCLUSIONS
  The present study confirms the findings of previous studies showing peak vulnerability to anaesthesia-induced neuronal cell death in the newborn forebrain. It also shows sustained susceptibility into adulthood in areas of continued neurogenesis, substantially expanding the previously observed age of vulnerability. The differential windows of vulnerability among brain regions, which closely follow regional peaks in neurogenesis, may explain the heightened vulnerability of the developing brain because of its increased number of immature neurones.
authors.affiliation: Department of Anesthesiology, Children's Hospital of Fudan University, Shanghai 201102, China Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: M
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Program in Neuroscience, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Hofacer
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: B
authors.initials: B
authors.lastname: Joseph
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Hughes
authors.affiliation: Heart Center, Children's Hospital of Fudan University, Shanghai 201102, China.
authors.forename: B
authors.initials: B
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Program in Neuroscience, University of Cincinnati, Cincinnati, OH 45221, USA Department of Anesthesiology, University of Cincinnati, Cincinnati, OH 45221, USA Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Danzer
authors.affiliation: Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Program in Neuroscience, University of Cincinnati, Cincinnati, OH 45221, USA Department of Anesthesiology, University of Cincinnati, Cincinnati, OH 45221, USA Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45221, USA pedsanesthesia@gmail.com.
authors.forename: A W
authors.initials: AW
authors.lastname: Loepke
mesh_terms: D000367:Age Factors; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane; D053148:Caspase 3
keywords: anaesthesia, paediatric; anaesthetics volatile, isoflurane; brain, injury; safety, drug; toxicity