New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio

Abstract

Altered function of kynurenine pathway has emerged recently as one of the factors contributing to the pathogenesis of depression. Neuroprotective kynurenic acid (KYNA) and neurotoxic 3-hydroxykynurenine (3-HK) are two immediate metabolites of L: -kynurenine. Here, we aimed to assess the hypothesis that antidepressant drugs that may change brain KYNA/3-HK ratio. In primary astroglial cultures, fluoxetine, citalopram, amitriptyline and imipramine (1-10 μM) increased de novo production of KYNA and diminished 3-HK synthesis (24 and 48, but not 2 h). RT-PCR studies revealed that Kat1, Kat2 and kynurenine-3-monooxygenase (Kmo) gene expressions were not altered after 2 h. At 24 h, the expression of Kat1 and Kat2 genes was enhanced by all studied drugs, whereas Kmo expression was diminished by citalopram, fluoxetine and amitriptyline, but not imipramine. After 48 h, the expression of Kat1 and Kat2 was further up-regulated, and Kmo expression was down-regulated by all antidepressants. The ratio KYNA/3-HK was increased by fluoxetine, citalopram, amitriptyline and imipramine in a time-dependent manner-the effect was not observed after 2 h, modest after 24 h and robust after 48 h incubation time. Our findings indicate that the action of antidepressants may involve re-establishing of the beneficial ratio between KYNA and 3-HK. Shift in the kynurenine pathway, observed after prolonged exposure to antidepressant drugs, may partly explain their delayed therapeutic effectiveness.

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

“…Regarding the a priori analyses, the ratios of KA/3HK and KA/QA, putative neuroprotective indices (Johansson et al, 2013;Kocki et al, 2012), were lower in the MDD group relative to the HCs (KA/3HK: t ¼ 2.42, p ¼ 0.019; KA/QA: t ¼ 2.04, p ¼ 0.047). However, after regressing out sex, age, and BMI, these differences no longer remained statistically significant (Figure 2).…”

“…Conversely, psychiatric medication may increase the synthesis of the potentially neuroprotective compound, KA, and/or decrease the synthesis of 3HK. (Kocki et al (2012) reported that 24-48 h of exposure to selective serotonin reuptake inhibitors or tricyclic antidepressant medications stimulated the de novo synthesis of KA and decreased 3HK production in astroglial cultures, thus resulting in an increase in the KA to 3HK ratio. Patients with schizophrenia had lower plasma concentrations of KA and higher plasma concentrations of 3HK than HCs, an effect that was ameliorated by 6 weeks of treatment with antipsychotic treatment such that a significant increase in the KA/3HK ratio was observed after treatment .…”

“…If this is the case, these volumes should be associated with increased concentrations of potentially neurotoxic kynurenine metabolites and/or decreased concentrations of potentially neuroprotective kynurenine metabolites. Because the effects of 'neurotoxic' metabolites on GM volumes may depend on the corresponding concentration of 'neuroprotective' metabolites, we maximized sensitivity by focusing a priori on the ratios of 'neuroprotective' to 'neurotoxic metabolites'-KA versus 3HK (KA/3HK) as well as KA versus QA (KA/ QA)-considered 'neuroprotective indices' (Johansson et al, 2013;Kocki et al, 2012). In addition, in order to reduce the probability of type I error while maintaining a hypothesisfree approach, we conducted a principal components analysis (PCA) and used the extracted principal components in a post hoc analysis.…”

Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study

“…Examples include anti-inflammatory treatments influencing immuno-inflammation such as cyclooxygensase-2 (COX-2) inhibitors, aspirin, minocycline and polyunsaturated fatty acids (Berk et al, 2013a, Fond et al, 2014, Muller, 2013 and antioxidant therapies to increase antioxidant defences and lower free radical damage such as n-acetyl cysteine, Ebselen, vitamin E and coenzyme-Q 10 (Berk et al, 2013b, Scapagnini et al, 2012. Interestingly, despite pharmaceutical antidepressants originally being heralded as targeting monoaminergic actions, there is also evidence that they can modulate immuno-inflammation, reduce oxidative stress, enhance neurotrophic factors and influence HPA activity (Abdel-Wahab and Salama, 2011, Andrade and Rao, 2010, Hannestad et al, 2011, Kocki et al, 2012, Schule, 2007.…”

Changes in the levels of kynurenic acid and selected proinflammatory cytokines after pharmacological treatment and electroconvulsive therapy (ECT) in patients with depressive disorder

“…They have found no statistically significant increase in KYNA levels in the serum of patients after treatment with different antidepressants, relative to the pre-treatment baseline [3]. The results of an animal model study carried out by Kocki et al [33] indicate that citalopram, fluoxetine and amitriptyline increase the ratio of kynurenic acid to 3-hydroxykynurenine. These investigators [33] have found that these antidepressants modulate the kynurenine pathway, and that their effects may be associated with the restoration of the beneficial KYNA /3-OH-KYN ratio.…”