Kynurenine pathway in Parkinson's disease—An update

Abstract

Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various in vitro studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its enzymes as it has an association with ageing and PD pathogenesis. Until now, very few studies have targeted the role of genetic mutations in abnormal KP metabolism in adverse conditions of PD. Therefore, the present review gives an updated research studies on KP in connection with PD. Moreover, the review emphasizes on the urge for the development of biomarkers and also this would be an initiative in generating an alternative therapeutic approach for PD.

Neurodegeneration in Multiple Sclerosis: Symptoms of Silent Progression, Biomarkers and Neuroprotective Therapy—Kynurenines Are Important Players

“…It was shown in animal studies that increased levels of QUIN and 3-HK can be found in both the brain and plasma [ 160 ]. Both KAT-I and KAT-II activity was lower in the plasma of PD patients, resulting in a lower level of KYNA observed [ 161 ]. Some studies found reduced levels of KYNA in the cortical regions and the basal ganglia of PD patients [ 162 ].…”

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

“…Various metabolomics studies have been performed to identify specific targets and biomarkers in PD pathogenesis. The metabolism of tryptophan (TRP) in association with the kynurenine pathway (KP) has been employed in multiple neurodegenerative and psychiatric diseases, cancer, inflammation, obesity, and diabetes [8]. The metabolites linked to KP are responsible for exerting physiological actions by interacting with intracellular or extracellular receptors in the peripheral and central nervous system (CNS) regions [8].…”

“…The metabolism of tryptophan (TRP) in association with the kynurenine pathway (KP) has been employed in multiple neurodegenerative and psychiatric diseases, cancer, inflammation, obesity, and diabetes [8]. The metabolites linked to KP are responsible for exerting physiological actions by interacting with intracellular or extracellular receptors in the peripheral and central nervous system (CNS) regions [8]. The activity at α7 nicotinic acetylcholine receptors and glutamate receptors is regulated by KP metabolites, which in turn influences the excitatory neurotransmission [9,10] and can further affect the immune-mediated responses, by acting at the transcription factor aryl hydrocarbon receptor (AhR) [10,11].…”

“…An important cofactor, nicotinamide adenine dinucleotide (NAD+), associated with energy metabolism, is produced as an end product of KP [12,13]. Large neutral amino acids transporters and enzymes modulate the concentration of KP metabolites in multiple tissues, where its actions are controlled by inflammation and exercise, along with microbiota composition in the gut [8].…”

Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

“…Kynurenine-3-monooxygenase (KMO, in the past also referred to as kynurenine-3-hydroxylase), has emerged as a therapeutic target for the treatment of numerous neurological disorders including Alzheimer’s disease (AD) [ 1 , 2 , 3 ], Huntington’s disease (HD) [ 4 , 5 ], Parkinson’s disease (PD) [ 6 ], schizophrenia [ 7 , 8 , 9 ], depression [ 10 , 11 ], and neuropathic pain [ 12 , 13 , 14 ] and its inhibition has been found to be protective against cancer [ 15 ] and multiple organ disorder in acute pancreatitis [ 16 ]. Located at a critical branch point in the main metabolic pathway of L-tryptophan, KMO facilitates the hydroxylation of L-kynurenine (L-kyn) to 3-hydroxy-kynurenine (3-HK) as opposed to the kynurenine aminotransferase (KAT) branch, which catalyzes the cyclization of L-kyn to form kynurenic acid (KynA) ( Figure 1 ).…”