Abstract
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.
Highlights
Affective disorders alter the mood of an individual
The translation of this diagram into a so-called Generalized Mass Action (GMA) model is technically straightforward [30,31] and yields the set of equations shown in S1 Supplement
A simulation with our model demonstrates that inhibition of kynurenine 3-monooxygenase (KMO) by 50% reduces the increase in the ratio of quinilinic acid (QUIN)/kynurenic acid (KYNA) (#31%) and increases KYNA/3-HK ("86%)
Summary
Affective disorders alter the mood of an individual. Most common among them is major depressive disorder (MDD). Up to 64% of recovered patients may suffer recurrent episodes of MDD [7], and only about 30 to 35% of adults treated with antidepressants go into remission [8]. Despite these disturbing statistics and the considerable impact of MDD on health and society, the biological basis for the pathophysiology of MDD is still obscure [9]
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