Quinolinic Acid and Nuclear Factor Erythroid 2-Related Factor 2 in Depression: Role in Neuroprogression

Abstract

Depression is an incapacitating neuropsychiatric disorder. The serotonergic system in the brain plays an important role in the pathophysiology of depression. However, due to delayed and/or poor performance of selective serotonin reuptake inhibitors in treating depressive symptoms, the role of the serotonergic system in depression has been recently questioned further. Evidence from recent studies suggests that increased inflammation and oxidative stress may play significant roles in the pathophysiology of depression. The consequences of these factors can lead to the neuroprogression of depression, involving neurodegeneration, astrocytic apoptosis, reduced neurogenesis, reduced plasticity (neuronal and synaptic), and enhanced immunoreactivity. Specifically, increased proinflammatory cytokine levels have been shown to activate the kynurenine pathway, which causes increased production of quinolinic acid (QA, an N-Methyl-D-aspartate agonist) and decreases the synthesis of serotonin. QA exerts many deleterious effects on the brain via mechanisms including N-methyl-D-aspartate excitotoxicity, increased oxidative stress, astrocyte degeneration, and neuronal apoptosis. QA may also act directly as a pro-oxidant. Additionally, the nuclear translocation of antioxidant defense factors, such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is downregulated in depression. Hence, in the present review, we discuss the role of QA in increasing oxidative stress in depression by modulating the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and thus affecting the synthesis of antioxidant enzymes.

Keywords: Nrf2; depression; oxidative stress; quinolinic acid; serotonin; tryptophan.

Figure 1

Schematic representation of tryptophan-kynurenine pathway. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KMO, kynurenine monooxygenase; KYNU, kynureninase; 3-HAO, 3-hydroxyanthranilate 3,4-dioxygenase; QPRT: quinolinate phosphoribosyl transferase.

Figure 2

Tryptophan metabolism in astrocytes, microglia and 5HT neuron. Tryptophan, precursor of serotonin is transported to brain with the aid of non-specific competitive L-type amino acid transporters. At homeostatic conditions tryptophan is metabolized to KA in astrocytes and 5HT in serotonergic neurons. KA is an NMDA and α7nAch receptor antagonist, hence acts as anti-excitotoxic and anticonvulsant, thus provide neuroprotection. Increased activation of inflammatory cascades either by psychological stress and LPS activates microglia (microgliosis). Increased inflammation due to psychological stress or LPS activates the enzymes of neurotoxic branch of kynurenine pathway in microglia. This leads to increased production of QA. Psychological stress and activation of inflammatory cascades diverts the metabolism of tryptophan towards QA. This shift hampers the neuroprotection provided by KA and decreases synthesis of 5HT in serotonergic neurons thus contribute to the depression pathophysiology. TRP, tryptophan; IDO, indoleamine-2,3-dioxygenase; KAT, kynurenine aminotransferase; TRPOH, tryptophan hydroxylase; AAADC, aromatic L-amino acid decarboxylase; 5HT, serotonin; 5HTP, 5-hydroxytryptophan; QA, quinolinic acid; KA, kynurenic acid; KYN, kynurenine; 3HK, 3-hydroxykynurenine; 3HAA, 3-hydroxyanthranilic acid; KMO, kynurenine monooxygenase; KYNU, kynureninase; 3HAO, 3-hydroxyanthranilate 3,4-dioxygenase.

Figure 3

Nrf2/ARE pathway during basal and stressed conditions. During homeostatic conditions Nrf2 remains in tethering with Keap1 and Cul3-Rbx1-E2 ligase and undergoes proteasome degradation through ubiquitination. In normal brain functioning, mild ROS production dissociates Nrf2 from Keap1 and translocate it to the nucleus. After nuclear translocation, it binds with ARE to transcribe genes of various antioxidants enzymes to combat deleterious effects of ROS. On contrary during chronic stress, increased activity of inflammatory cascades and GSK-3β increased Nrf2 proteasome degradation via ubiquitination. Nrf2, nuclear factor (erythroid-derived 2)-like 2; Keap1, Kelch-like ECH associated protein-1; Cul-3, cullin 3; ROS, reactive oxygen species; ARE, antioxidant response element; Rbx1, ring box-1; E2, E2 ubiquitin-conjugating enzyme; Ub, ubiquitin.

Figure 4

Interaction between QA and Nrf2 in depression. In chronic stress conditions, increased proinflammatory cytokines lead to microgliosis. Increased proinflammatory cytokines activate IDO (enzyme catalyzing first rate-limiting step of KP) and shift tryptophan metabolism from serotonin synthesis to KP in microglia. Elevated levels of QA further increases oxidative stress through NMDA agonistic activity and secondly might be through directly inhibiting nuclear translocation of Nrf2 and hence causes increased proteasome degradation of Nrf2 which ultimately led to decreased antioxidant levels and increased oxidative stress. QA also causes degeneration of astrocytes thus hampering protection and nutritional support to neurons. All this together lead to degeneration of 5HT neurons and decreased 5HT synthesis which results in depression. On the other hand mild oxidative stress stabilizes Nrf2 and increases Nrf2 transcribed antioxidant enzymes. IDO, indoleamine-2,3-dioxygenase; KP, kynurenine pathway; QA, quinolinic acid; KA, kynurenic acid; Nrf2, nuclear factor (erythroid-derived 2)-like 2; 5HT, serotonin.