title: Effects of ketamine administration on the phosphorylation levels of CREB and TrKB and on oxidative damage after infusion of MEK inhibitor.
abstract: BACKGROUND
  Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, this study evaluated the effects of the administration of ketamine on the phosphorylation of TrKB and CREB, and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc) rats, after the inhibition of MAPK pathway (PD184161).
  
  
  METHODS
  Male adult Wistar rats were submitted to a surgical procedure to receive a single dose of a pharmacological inhibitor of MAPK (PD184161) at a dose of (0.1μg/μl) or vehicle. Then, they were divided: 1) vehicle+saline; 2) inhibitor PD184161+saline; 3) vehicle+ketamine 15mg/kg; and 4) inhibitor PD184161+ketamine 15mg/kg.
  
  
  RESULTS
  MEK inhibitor and ketamine increased the phosphorylation of the transcription factor cAMP response element-binding protein (pCREB) and neurotrophic factor/tropomyosin related kinase B receptor (pTrKB) in the PFC, and decreased pCREB in the hippocampus. The MEK inhibitor abolished ketamine's effects in the hippocampus. In the amygdala, pCREB was decreased, and pTrKB was increased after MEK inhibitor plus ketamine. Ketamine increased the thiobarbituric acid reactive species (TBARS) in the PFC, hippocampus, amygdala, and NAc; MEK inhibitor antagonized these effects. The carbonyl was increased in the PFC by both ketamine and MEK inhibitor, but inhibitor infusion plus ketamine administration reduced this effect. In the amygdala, MEK inhibitor increased carbonyl.
  
  
  CONCLUSIONS
  Ketamine's effects on pCREB, pTrKB, and oxidative stress are mediated, at least in part, by a mechanism dependent of MAPK signaling inhibition.
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil; Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, USA. Electronic address: gislainezilli@hotmail.com.
authors.forename: Gislaine Z
authors.initials: GZ
authors.lastname: Réus
authors.affiliation: Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, USA.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Abaleira
authors.affiliation: Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Titus
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Camila O
authors.initials: CO
authors.lastname: Arent
authors.affiliation: Laboratório de Fisiopatologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Monique
authors.initials: M
authors.lastname: Michels
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Jaine R
authors.initials: JR
authors.lastname: da Luz
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Maria Augusta B
authors.initials: MA
authors.lastname: dos Santos
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Anelise S
authors.initials: AS
authors.lastname: Carlessi
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Beatriz I
authors.initials: BI
authors.lastname: Matias
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Livia
authors.initials: L
authors.lastname: Bruchchen
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Amanda V
authors.initials: AV
authors.lastname: Steckert
authors.affiliation: Laboratório de Saúde Coletiva, Programa de Pós Graduação em Saúde Coletiva, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Luciane B
authors.initials: LB
authors.lastname: Ceretta
authors.affiliation: Laboratório de Fisiopatologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil.
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.affiliation: Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Brazil; Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, USA.
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D007262:Infusions, Intravenous; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism*
chemical_list: C488185:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide; D000814:Aniline Compounds; D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D007649:Ketamine; D020813:Receptor, trkB; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: CREB; Depression; Ketamine; MEK; Oxidative stress