Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases

2010 ◽  
pp. 149-176 ◽  
Author(s):  
Stephen Courtney ◽  
Andreas Scheel
Keyword(s):  
Neurodegenerative Diseases ◽  
Kynurenine Pathway ◽  
Potential Treatment

scholarly journals Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

2021 ◽  
Vol 22 (1) ◽  
pp. 403
Author(s):  
Fanni Tóth ◽  
Edina Katalin Cseh ◽  
László Vécsei
Keyword(s):  
Neurodegenerative Diseases ◽  
Lipoic Acid ◽  
Kynurenic Acid ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Structural Diversity ◽  
Kynurenine Pathway ◽  
Glutamate Excitotoxicity ◽  
Neuroprotective Agents ◽  
Starting Point

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

scholarly journals Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

2016 ◽  
Vol 113 (19) ◽  
pp. 5435-5440 ◽  
Author(s):  
Carlo Breda ◽  
Korrapati V. Sathyasaikumar ◽  
Shama Sograte Idrissi ◽  
Francesca M. Notarangelo ◽  
Jasper G. Estranero ◽  
...  
Keyword(s):  
Quinolinic Acid ◽  
Neurodegenerative Disorders ◽  
Kynurenic Acid ◽  
Therapeutic Potential ◽  
Fruit Fly ◽  
Kynurenine Pathway ◽  
Locomotor Performance ◽  
Potential Treatment ◽  
Regulatory Enzymes ◽  
Therapeutic Benefits

Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway—kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP—the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington’s disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer’s and Parkinson’s disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases

2013 ◽  
Vol 21 (23) ◽  
pp. 7435-7452 ◽  
Author(s):  
Pierre Koch ◽  
Rhalid Akkari ◽  
Andreas Brunschweiger ◽  
Thomas Borrmann ◽  
Miriam Schlenk ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Potential Treatment ◽  
Multiple Target

scholarly journals Kynurenic Acid Levels are Increased in the CSF of Alzheimer’s Disease Patients

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 571 ◽  
Author(s):  
Marta González-Sánchez ◽  
Javier Jiménez ◽  
Arantzazu Narváez ◽  
Desiree Antequera ◽  
Sara Llamas-Velasco ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Healthy Subjects ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Healthy Controls ◽  
Specific Increase ◽  
Normal Controls ◽  
Lateral Sclerosis

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.

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