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

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.

The Role of Kiwifruit in Supporting Psychological Well-Being: A Rapid Review of the Literature

“…These include the small sample size ( N = 35) of young adult males and the small sample size ( n = 8) included in sub-analyses [ 57 ], restricting recruitment to otherwise healthy adults aged 18–35 years old [ 56 , 57 ] and lack of a washout period [ 57 ]. Furthermore, micronutrients (i.e., folate, zinc, selenium, magnesium and serotonin) found in gold kiwifruit that have been implicated in the pathophysiology of depression [ 71 , 72 , 73 , 74 ] were not isolated or measured by either study, leaving the potential relative contribution to mood outcomes from these nutrients undetermined.…”

“…Whilst Vitamin C has been defined as a putative pathway for the observed benefits of kiwifruit intake, this hypothesis does not preclude other nutritional aspects that may contribute to observed effects. Future studies would benefit from investigating the individual or synergistic contribution to psychological well-being from other micronutrients found at dietary relevant levels in gold kiwifruit with established links to depression pathogenesis [ 71 , 72 , 73 , 74 ]. For example, gold kiwifruit contain nutritionally relevant levels of vitamin E, a micronutrient linked to mood regulation [ 80 ] and thought to act synergistically with vitamin C in an antioxidant capacity [ 81 ].…”

Kynurenine and oxidative stress in children having learning disorder with and without attention deficit hyperactivity disorder: possible role and involvement

“…The excess KYN level could reflect deficits in its conversion to active brain modulators. The KYN system has been reported to influence the brain by reducing the action of dopamine, acetylcholine, and gamma amino butyric acid [ 27 , 28 ]. Balanced levels of these neurotransmitters are essential for appropriate brain function and adequate cognitive performance.…”

Hippocampal Proteomics Reveals the Role of Glutamatergic Synapse Activation in the Depression Induced by Perfluorooctane Sulfonate

“…Parkinson's disease is a progressive neurodegenerative movement disorder primarily resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc), while a major factor contributing to the etiology of depression is a neurochemical imbalance of the dopaminergic and serotonergic systems. 45 Ribosomes are essential for the acquisition of all the functional proteins, 46 not only in depression. Various neurotransmitters have been implicated in retrograde signaling such as the release of glutamate 47 and what has to do with it is that abnormal secretion and inactivation of neurotransmitters has been an important factor in the occurrence of depression.…”