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Effects of Ketamine Administration on the Phosphorylation Levels of CREB and TrKB and on Oxidative Damage After Infusion of MEK Inhibitor

Effects of Ketamine Administration on the Phosphorylation Levels of CREB and TrKB and on Oxidative Damage After Infusion of MEK Inhibitor

Gislaine Z Réus, Helena M Abaleira, Stephanie E Titus, Camila O Arent, Monique Michels, Jaine R da Luz, Maria Augusta B dos Santos, Anelise S Carlessi, Beatriz I Matias, Livia Bruchchen, Amanda V Steckert, etc.

Pharmacol Rep. 2016 Feb;68(1):177-84.

PMID: 26721370

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.
Conclusion:
Ketamine's effects on pCREB, pTrKB, and oxidative stress are mediated, at least in part, by a mechanism dependent of MAPK signaling inhibition.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP212631679	PD-184161		212631-67-9	Price

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