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.

Saturated Fatty Acid Intake Is Associated With Increased Inflammation, Conversion of Kynurenine to Tryptophan, and Delta-9 Desaturase Activity in Healthy Humans

“…Due to the role of inflammation in the development and progression of several disease states we hope these findings can increase the awareness of health professionals to the probability that SFA consumption will accelerate tryptophan catabolism via the kynurenine pathway creating a range of negative health sequelae. 41 …”

Albiflorin Attenuates Mood Disorders Under Neuropathic Pain State by Suppressing the Hippocampal NLRP3 Inflammasome Activation During Chronic Constriction Injury

“…Moreover, Nrf2 attenuates the activation of NF-κB; this leads to suppression of the inflammasome activity by downregulating the expression of the inflammasome components NLRP3, caspase-1, and pro-IL-1β ( Li et al, 2008 ; Chu et al, 2019 ; Dang et al, 2019 ). In addition to its role in NLRP3 inflammasome, the Kea1-Nrf2 pathway is also involved in depression in preclinical and clinical studies ( Bansal et al, 2019 ; Chu et al, 2019 ; Dang et al, 2019 ; Swanson et al, 2019 ; Zborowski et al, 2020 ), which implies that interrupting the Keap1-NRF2 protein–protein interaction might be a potential therapy against depression. Furthermore, a recent animal study indicated that the Nrf2-NLRP3 signaling pathway, which is responsible for adjusting inflammation levels, plays a vital role in the depression induced by environmental factors ( Chu et al, 2019 ).…”

“…In addition to NLRP3, the Kelch-like ECH associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is also involved in neuropathic pain and depression in preclinical and clinical studies ( Braidy et al, 2018 ; Li et al, 2018 ; Bansal et al, 2019 ; Chu et al, 2019 ; Dang et al, 2019 ; Swanson et al, 2019 ; Zborowski et al, 2020 ; Zhou et al, 2020a , 2020b ). Keap1 suppresses Nrf2 activity under physiological conditions, whereas Nrf2 is liberated from Keap1-mediated suppression on exposure to stresses.…”

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges

“…In fact, an increase in QA concentration in the brain and cerebrospinal fluid of depressive individuals suffering from suicide was already found [48,49]. In addition, increased QA concentration has been associated with oxidative stress and lipid peroxidation [50].…”