Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

Abstract

The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO), but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme, but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with antiinflammatory properties are unlikely to act by direct inhibition of IDO, but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of 6 antiinflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other 5 dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD. TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal antiinflammatory drugs. The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.

Life-Threatening Cardiogenic Shock Related to Venlafaxine Poisoning—A Case Report with Metabolomic Approach

“…The promotion of the kynurenine pathway has been reported to result in the inhibition of serotonin synthesis [ 51 ], thus strongly supporting the notion that venlafaxine may decrease plasma serotonin concentrations by activating the kynurenine pathway. Some metabolites in the kynurenine pathway, including kynurenic acid, have been described as being neuroprotective in the depression setting [ 52 , 53 , 54 , 55 , 56 ]. Interestingly, kynurenic acid was the only negatively correlated metabolite with venlafaxine.…”

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

“…Indeed, inflammatory cytokines released in the process of COVID-19 inflammation activate both the HPA–axis and the IDO enzyme, increasing the levels of toxic metabolites of the Kyn pathway, which increases overall neuroinflammation and neuronal death, promoting depressive conditions [ 52 ]. Additionally, antidepressants with anti-inflammatory properties inhibit IDO induction by decreasing the levels of proinflammatory cytokines in immune-activated individuals, contributing to attenuation of depressive symptoms [ 53 ]. The role of the immune system in depression is also supported by the homeostasis of glutamatergic neurotransmission, which can be regulated by the QA/Kyna ratio, synthetized by microglia and astrocytes, respectively [ 54 ].…”

Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder

“…Further evidence of the targeting of TDO by antidepressant drugs was provided by our group, using molecular docking in silico : A technique for screening potential inhibitors of target proteins[ 14 , 15 ], but is also useful to confirm known inhibitors. We demonstrated high docking scores (strong binding) of many antidepressants, including amoxapine, citalopram, fluoxetine, fluvoxamine, moclobemide, paroxetine, seproxetine, sertraline[ 16 ], tianeptine and venlafaxine, but not the non-antidepressant drugs pargyline and mefenamic acid[ 17 ] to the crystal structure of TDO, but no docking to that of the extrahepatic IDO. Thus, antidepressants target TDO and this could explain their ability to restore serotonin homeostasis, at least in part, by reversing the defective serotonin synthesis.…”

“…As this cytokine is an IDO inducer, the concept that serotonin deficiency in MDD is underpinned by IDO induction secondarily to inflammation was born. Extrapolating from hepatitis C to MDD was however unwise, given that Trp metabolism is already compromised by this virus and the use of IFN-α can only potentiate the effect of the virus on Trp metabolism, in particular IDO induction[ 17 ]. Although many studies of the immune status in MDD followed, recent studies suggested that not all MDD patients are immune-activated and, when present, inflammation is mild and/or transient and its reversal does not reflect clinical outcome[ 28 , 29 ].…”