Evaluation of the pharmacodynamic effects of Ketamine on neurotransmitter levels and CREB/BDNF expression in rat brain.
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Date
2020
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Abstract
Mental disorders contribute to 13% of the global burden of disease. With major depressive
disorder (MDD) expected to be the most significant contributor by 2030, the economic and
social impact of this burden will be substantial. There have been various factors linked to the
underlying pathophysiology of MDD, including a deficit in individual vital neurotransmitter
connections between specific neurons, and alterations in the expression of the transcription
factors cyclic AMP response element-binding protein (CREB) and the brain-derived
neurotrophic factor (BDNF) in the brain. Ketamine, an N-methyl-D-aspartate receptor
(NMDAR) rantagonist and an -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor (AMPAR) stimulator has officialy been used as an anesthetic and analgesic drug since
the 1970s, until recently when it was approved for the management and treatment of MDD.
Ketamine works by altering and rebalancing the monoaminergic, glutamatergic and GABArgic
sytems to stimulate new synaptic connections, better memory, and improved brain plasticity.
However, there are limited published studies that demonstrate the direct relationship between
ketamine, brain neurotransmitters levels, gene and protein expression in the management of
MDD.
In this study, we investigated the pharmacodynamic effects of ketamine in the brain by
assessing changes in monoaminergic, glutaminergic and GABAergic neurotransmitter levels
using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we
investigated the links between ketamine and the expression of transcription factors, cyclic AMP
response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in
treatment of depression using quantitative real-time polymerase chain reaction (qPCR)
analysis. Twenty-one healthy male Sprague-Dawley (SD) rats were administered 15mg/kg of
ketamine via intraperitoneal administration at different time points (N = 3 per time point).
Experimental animals were euthanized by decapitation post-administration of ketamine, and
brain samples were harvested for analysis.
As per LC-MS/MS and qPCR, the pharmacodynamic results demonstrated that ketamines
anti-depressive mechanism of action is due to alteration of the glutamatergic system which
occurs via the disinhibition of glutamate release, which further boosts central nervous
synaptogenesis, hence maintaining the in-balance neurotransmitters and genes associated with
the pathophysiology of depression.
Description
Masters Degree. University of KwaZulu-Natal, Durban.