title: Propofol at clinically relevant concentrations increases neuronal differentiation but is not toxic to hippocampal neural precursor cells in vitro.
abstract: BACKGROUND
  Propofol in the early postnatal period has been shown to cause brain cell death. One proposed mechanism for cognitive dysfunction after anesthesia is alteration of neural stem cell function and neurogenesis. We examined the effect of propofol on neural precursor or stem cells (NPCs) grown in vitro.
  
  
  METHODS
  Hippocampal-derived NPCs from postnatal day 2 rats were exposed to propofol or Diprivan. NPCs were then analyzed for bromodeoxyuridine incorporation to measure proliferation. Cell death was measured by lactate dehydrogenase release. Immunocytochemistry was used to evaluate the expression of neuronal and glial markers in differentiating NPCs exposed to propofol.
  
  
  RESULTS
  Propofol dose dependently increases the release of lactate dehydrogenase from NPCs under both proliferating and differentiating conditions at supraclinical concentrations (more than 7.1 µM). Both Diprivan and propofol had the same effect on NPCs. Propofol-mediated release of lactate dehydrogenase is not inhibited by blocking the γ-aminobutyric acid type A receptor or extracellular calcium influx and is not mediated by caspase-3/7. Direct γ-aminobutyric acid type A receptor activation did not have the same effect. In differentiating NPCs, 6 h of propofol at 2.1 µM increased the number neurons but not glial cells 4 days later. Increased neuronal differentiation was not blocked by bicuculline.
  
  
  CONCLUSIONS
  Only supraclinical concentrations of propofol or Diprivan kill NPCs in culture by a non-γ-aminobutyric acid type A, noncaspase-3 mechanism. Clinically relevant doses of propofol increase neuronal fate choice by a non-γ-aminobutyric acid type A mechanism.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94143-0542, USA. sallj@anesthesia.ucsf.edu
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Sall
authors.forename: Greg
authors.initials: G
authors.lastname: Stratmann
authors.forename: Jason
authors.initials: J
authors.lastname: Leong
authors.forename: Elliott
authors.initials: E
authors.lastname: Woodward
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bickler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects* / Q000254:growth & development; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D015742:Propofol / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015742:Propofol