The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson’s Disorder and Therapeutic Implications

Abstract

Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson’s disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA—which antagonizes QUIN actions—primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

“…KP alterations have been identified as components in the etiology of AD and other stated neurodegenerative diseases ( 19 – 21 ). 3-HK and KYNA, two metabolites of TRP, have excitotoxic and neuroprotective effects on neural cells, respectively ( 22 – 24 ). The enzymes IDO and KMO have a pivotal role in 3-HK production by the KP, and can be induced through pro-inflammatory cytokines ( 25 ).…”

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

“…KMO (located in the outer mitochondrial membrane), the main synthetase of the QUIN pathway, converts kynurenine to 3-HK. This component crosses the BBB and increases the substrate required for QUIN production, producing neuronal apoptosis, free radical generation, and oxidative stress damage in the brain at nanomolar concentrations, leading to elevated metal toxicity in rat astrocyte cultures and effectively synergizing the neurotoxic effects of QUIN ( 22 ). Subsequently, 3-HK is formed into 3-hydroxyanthranilic acid (3-HAA) by the action of KYNU.…”

Nutraceuticals and Physical Activity as Antidepressants: The Central Role of the Gut Microbiota

“…The commensal gut bacteria promote the colonic serotonin biosynthesis and directly utilize tryptophan to produce serotonin. Tryptophan can be degraded via the kynurenine pathway in the liver, producing kynurenic acid (KYNA) and quinolinic acids (QUIN) with neuroprotective and neurotoxic functions, respectively; these molecules can cross the blood–brain barrier [ 42 ]. Therefore, the activation of the kynurenine pathway limits the tryptophan bioavailability for serotonin production and modulates brain functions, influencing neuropsychiatric disorders like depression [ 43 ].…”