title: Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats.
abstract: BACKGROUND
  Ketamine-induced neuroapoptosis has been attributed to diverse stress-related mechanisms. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional kinase that is active in neuronal development and linked to neurodegenerative disorders. We hypothesized that ketamine would enhance GSK-3β-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3β, would attenuate this response in vivo.
  
  
  METHODS
  Protein levels of cleaved caspase-3, protein kinase B (AKT), GSK-3β, and cyclin D1 were measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 h exposure to ketamine. A cohort of rat pups was randomized to a 6 h exposure to ketamine with and without lithium. Neuroapoptosis was measured by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and phosphorylated forms of AKT, GSK-3β, and cyclin D1 (cell cycle protein) were also measured.
  
  
  RESULTS
  Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which corresponded to decreases in phosphorylated AKT and GSK-3β. Co-administration of lithium with ketamine attenuated this response.
  
  
  CONCLUSIONS
  Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3β phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3β is activated during this ketamine-induced neuroapoptosis.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Baek
authors.forename: X H
authors.initials: XH
authors.lastname: Han
authors.forename: P
authors.initials: P
authors.lastname: Shoureshi
authors.forename: S G
authors.initials: SG
authors.lastname: Soriano
mesh_terms: D000778:Anesthetics, Dissociative / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D007649:Ketamine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000778:Anesthetics, Dissociative; D018696:Neuroprotective Agents; D007649:Ketamine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D018021:Lithium Chloride
keywords: AKT; apoptosis; glycogen synthase kinase-3β; ketamine; lithium; protein kinase B