Kynurenine monooxygenase inhibition and associated reduced quinolinic acid reverses depression-like behaviour by upregulating Nrf2/ARE pathway in mouse model of depression: In-vivo and In-silico studies

• Published in: Neuropharmacology 2022-09, Vol.215, p.109169-109169, Article 109169
• Main Authors: Bansal, Yashika, Singh, Raghunath, Sodhi, Rupinder Kaur, Khare, Pragyanshu, Dhingra, Richa, Dhingra, Neelima, Bishnoi, Mahendra, Kondepudi, Kanthi Kiran, Kuhad, Anurag
• Format: Article
• Language: English
• Subjects: Agitated depression; Depression; Inflammation; Kynurenine pathway; Nuclear factor erythroid 2 related factor 2; Oxidative stress; Quinolinic acid
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109169

Kynurenine pathway, a neuroimmunological pathway plays a substantial role in depression. Consistently, increased levels of neurotoxic metabolite of kynurenine pathway; quinolinic acid (QA) found in the suicidal patients and remitted major depressive patients. QA, an endogenous modulator of N-methyl-d-aspartate receptor is produced by microglial cells, may serve as a potential candidate for a link between antioxidant defence system and immune changes in depression. Further, nuclear factor (erythroid-derived 2) like 2 (Nrf2), an endogenous antioxidant transcription factor plays a significant role in maintaining antioxidant homeostasis during basal and stress conditions. The present study was designed to explore the effects of KMO-inhibition (Kynurenine monooxygenase) and association of reduced QA on Keap1/Nrf2/ARE pathway activity in olfactory bulbectomized mice (OBX-mice). KMO catalysis the neurotoxic branch of kynurenine pathway directing the synthesis of QA. KMO inhibitionshowed significant reversal of depressive-like behaviour, restored Keap-1 and Nrf2 mRNA expression, and associated antioxidant levels in cortex and hippocampus of OBX-mice. KMO inhibition also increased PI3K/AKT mRNA expression in OBX-mice. KMO inhibition and associated reduced QA significantly decreased inflammatory markers, kynurenine and increased the 5-HT, 5-HIAA and tryptophan levels in OBX-mice. Furthermore, molecular docking studies has shown good binding affinity of QA towards ubiquitin proteasome complex and PI3K protein involved in Keap-1 dependent and independent proteasome degradation of Nrf2 respectively supporting our in-vivo findings. Hence, QA might act as pro-oxidant through downregulating Nrf2/ARE pathway along with modulating other pathways and KMO inhibition could be a potential therapeutic target for depression treatment. [Display omitted] •Quinolinic acid (QA) level was increased in olfactory bulbectomized mouse (OB) model.•KMO inhibition upregulated Nrf2 in OB model.•Nrf2 is modulated via Keap-1 dependent & independent mechanism by QA synthesis inhibition in OB model.•Molecular docking studies showed potential binding of QA with Keap-1 and PI3K protein.