A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression.

A major factor contributing to the etiology of depression is a neurochemical imbalance of the dopaminergic and serotonergic systems, which is caused by persistently high levels of circulating stress hormones. Here, a computational model is proposed to investigate the interplay between dopaminergic and serotonergic-kynurenine metabolism under cortisolemia and its consequences for the onset of depression. The model was formulated as a set of nonlinear ordinary differential equations represented with power-law functions. Parameter values were obtained from experimental data reported in the literature, biological databases, and other general information, and subsequently fine-tuned through optimization. Model simulations predict that changes in the kynurenine pathway, caused by elevated levels of cortisol, can increase the risk of neurotoxicity and lead to increased levels of 3,4-dihydroxyphenylaceltahyde (DOPAL) and 5-hydroxyindoleacetaldehyde (5-HIAL). These aldehydes contribute to alpha-synuclein aggregation and may cause mitochondrial fragmentation. Further model analysis demonstrated that the inhibition of both serotonin transport and kynurenine-3-monooxygenase decreased the levels of DOPAL and 5-HIAL and the neurotoxic risk often associated with depression. The mathematical model was also able to predict a novel role of the dopamine and serotonin metabolites DOPAL and 5-HIAL in the ethiology of depression, which is facilitated through increased cortisol levels. Finally, the model analysis suggests treatment with a combination of inhibitors of serotonin transport and kynurenine-3-monooxygenase as a potentially effective pharmacological strategy to revert the slow-down in monoamine neurotransmission that is often triggered by inflammation. Author summary: According to the World Health Organization, major depressive disorder (MDD) was in 2014 the fourth leading cause of disability in people between the ages of 15 and 44 years. MDD is responsible for about 1 million suicides per year and associated with a number of other medical conditions such as coronary disease, diabetes, and Alzheimer's disease. While MDD has been studied for a long time, molecular details of its pathophysiology are still scarce. Computational models offer a powerful opportunity to assist neuropsychiatric disorder research, as they permit the representation of large sets of physiological, cellular and biochemical phenomena through mathematical equations that can be simulated in a very efficient fashion and have the capacity to provide testable hypotheses. Here, we introduce a computational model of relevant biochemical pathways associated with high levels of circulating stress hormone, as they are observed in MDD. The model captures known observations well and demonstrates how increased levels of internally produced toxic agents, such as various kynurenines, DOPAL and 5-HIAL, can lead to dysregulation of key enzymes. These insights suggest new hypotheses for model-driven experiments, as well as novel potential targets for pharmacological intervention. [ABSTRACT FROM AUTHOR]