DalviGarcia2021 - Dopaminergic and Serotonergic-Kynurenine model

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Short description
A mathematical model predicting 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.
Related Publication
  • A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression
  • Felipe Dalvi-Garcia, Luis L. Fonseca, Ana Tereza R. Vasconcelos, Cecilia Hedin-Pereira, Eberhard O. Voit
  • PLOS Computational Biology , 5/ 2021 , Volume 17 , Issue 5 , pages: e1008956 , DOI: 10.1371/journal.pcbi.1008956
  • School of Medicine and Surgery
  • 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.
Felipe Dalvi-Garcia, Krishna Kumar Tiwari

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Model files

main.py Main file: experiments and graphs are generated by running this file 10.32 KB Preview | Download

Additional files

myfunctions.py File with functions developed for this model and used by the main file 13.91 KB Preview | Download

  • Model originally submitted by : Felipe Dalvi-Garcia
  • Submitted: 11-May-2021 09:11:07
  • Last Modified: 11-May-2021 09:11:07
  • Version: 4 public model Download this version
    • Submitted on: 11-May-2021 09:11:07
    • Submitted by: Krishna Kumar Tiwari
    • With comment: added model short description and publication abstract.