title: Noxious stimulation attenuates ketamine-induced neuroapoptosis in the developing rat brain.
abstract: BACKGROUND
  Ketamine induces neuroapoptosis in neonatal rodents. However, these experimental paradigms were performed without concurrent noxious stimulation, a condition that does not reflect the interaction of anesthesia and surgical stimulation. Noxious stimulation with and without concurrent analgesic drugs has been shown to have divergent patterns of neuronal activation and cell death. We hypothesized that concurrent noxious stimulation would attenuate ketamine-induced caspase-3 activation.
  
  
  METHODS
  Postnatal day 7 Sprague-Dawley rat pups were randomized to a 6-h exposure to ketamine with and without peripheral noxious stimulation by intraplantar injection of complete Freund's adjuvant. A cohort of naïve rat pups with and without complete Freund's adjuvant injections served as control subjects. Neuroapoptosis was measured by cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining. In order to determine if concurrent noxious simulation altered the expression of cell survival and cell cycle proteins, levels of protein kinase B and glycogen synthase kinase-3β and cyclin D1 were measured.
  
  
  RESULTS
  Ketamine induced a significant increase in cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining with increases in cyclin D1 levels. Concurrent noxious stimulation with ketamine attenuated caspase-3 activation and maintained cyclin D1 levels. Phosphorylation of protein kinase B and glycogen synthase kinase-3β was not definitively altered under these conditions.
  
  
  CONCLUSIONS
  The administration of ketamine with concurrent noxious stimulation results in the attenuation of the neuroapoptotic response. These findings suggest that concurrent surgery and procedural pain attenuates ketamine-induced neuroapoptosis.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jia-Ren
authors.initials: JR
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Chongwha
authors.initials: C
authors.lastname: Baek
authors.forename: Xiao Hui
authors.initials: XH
authors.lastname: Han
authors.forename: Umeshkumar
authors.initials: U
authors.lastname: Athiraman
authors.forename: Sulpicio G
authors.initials: SG
authors.lastname: Soriano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D019938:Cyclin D1 / Q000032:analysis; D005620:Freund's Adjuvant / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis; D000071679:Glycogen Synthase Kinase 3 beta; D007649:Ketamine / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C530106:Ccnd1 protein, rat; D019938:Cyclin D1; D007649:Ketamine; D005620:Freund's Adjuvant; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3