Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour

Abstract

The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accompanying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression associated with stress-related disorders in which there is evidence for KP activation.

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Chronic co-treatment of rats with the TDO2 inhibitor allopurinol prevented restraint stress from decreasing FST activity (Gibney et al, 2014). Now the current study provides some of the first evidence for the reversal of behavioural effects of stress-induced IDO1-KYN pathway activation.…”

“…Tdo2 expression in liver, the major Tdo2-expressing tissue, was increased in CSD mice. Rats exposed to repeated physical restraint exhibit increased liver TDO, brain cortex Tdo2 mRNA expression, and plasma KYN (Gibney et al, 2014). Mice exposed to acute acoustic + restraint stress exhibited increased Ido1 mRNA expression in spleen, ileum and brain, dependent on increased plasma TNF- and IFN-, that was apparent at 12 h after stress termination and returned to basal expression after 24 h 28 (Kiank et al, 2010).…”

“…MDD patients exhibit up-regulation of TNF and other inflammation genes in peripheral blood mononuclear cells; the expression levels of these genes correlate with amygdala reactivity to fearful faces (Savitz et al, 2013). One candidate stress-activated inflammation pathway, including for induction of hyperfearfulness, is the kynurenine pathway: increased TNF-, IL-6 and interferon- (IFN-) increase expression of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2), enzymes expressed by immune cells and other cell types in various tissues, that promote tryptophan (TRP) catabolism to kynurenine (KYN) in periphery and brain (Dai and Zhu, 2010;Gibney et al, 2014;Robinson et al, 2003;Vecsei et al, 2013;Werner-Felmayer et 6 al., 1989). KYN is further metabolized to, among others, 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA), catabolites that can contribute to oxidative stress, excitotoxicity, and neuroprotection (for review: (Chiarugi et al, 2001;Haroon et al, 2012;Schwarcz et al, 2012).…”

Aldosterone Signals the Onset of Depressive Behaviour in a Female Rat Model of Depression along with SSRI Treatment Resistance

“…The increase in the kynurenine-to-kynurenic acid ratio in our model may be due to increased corticosterone secretion through an action on IDO/tryptophan 2,3-dioxygenase (TDO) activity either directly or indirectly via changes in pro-inflammatory cytokines, such as IL-6 found here in the present study [22,51]. In a most recent study, repeated exposure to stress resulted in increased immobility in the FST which was accompanied by an increase in circulating corticosterone and expression of hepatic TDO activity and was associated with a reduction of serum TRP and raised kynurenine concentrations [52]. Co-treatment with the TDO antagonist allopurinol reversed these findings.…”

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

“…Association of depression with the increased production of cortisol (Leonard 2005 ) is described elsewhere and might be further supported by the results of recent animal experiments (Gibney et al 2014 ). Discovery of infl ammation-inducible IDO added another mechanism of upregulation of KYN formation from TRP in depression (Hayaishi 1976 ).…”