Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Abstract

Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP’s metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

The role of indoleamine 2,3-dioxygenase 1 in early-onset post-stroke depression

“…Our finding was further supported by a preclinical study that denoted increased IDO expression in the nucleus accumbens, hippocampus, and hypothalamus of PSD-like phenotype mice (29). There are several underlying mechanisms that may account for the association of IDO1 with PSD: the elevated levels of proinflammatory cytokines after stroke upregulate IDO1 expression that causes the depletion of serotonin precursor tryptophan and increased neurotoxic kynurenine metabolite (quinolinic acid), an agonist of NMDA receptors, leading to the occurrence of depression (14,(30)(31)(32). IDO1 has been seen as a central hub linking immuneinflammatory processes to the monoaminergic (33) and glutamatergic systems implicated in depression (14).…”

“…There are several underlying mechanisms that may account for the association of IDO1 with PSD: the elevated levels of proinflammatory cytokines after stroke upregulate IDO1 expression that causes the depletion of serotonin precursor tryptophan and increased neurotoxic kynurenine metabolite (quinolinic acid), an agonist of NMDA receptors, leading to the occurrence of depression (14,(30)(31)(32). IDO1 has been seen as a central hub linking immuneinflammatory processes to the monoaminergic (33) and glutamatergic systems implicated in depression (14). Our results, taken together, supported that the interactions of cytokine-serotonin and -glutamate via IDO1 could play a key role in PSD (3, 4).…”

“…IDO1 is an enzyme strictly regulated by cytokines and can be expressed in a variety of cells throughout the body in response to immunological signals, including IFN-g, TNF-a, IL-1b, IL-2, and IL-6 stimulation (6,11). It has been well-established that IDO1 plays an important role in the etiology of depression through two mechanisms (6,12), one is that the overactivated IDO1, an initial and key ratelimiting enzyme of the tryptophan catabolite pathway, tends to direct tryptophan down the kynurenine pathway that releases quinolinic acid, a powerful N-methyl-D-aspartate (NMDA) receptor agonist with definite neurotoxic effects which is involved in the onset of depression (13,14), and the other is that IDO1 shunts tryptophan from the serotonin synthesis route, thereby favoring depression (15). These observations indicate that IDO1 activation is relatively unique to inflammation-induced depression (16).…”