scholarly journals Kynurenic acid in neurodegenerative disorders—unique neuroprotection or double‐edged sword?

2021 ◽  
Author(s):  
Aleksandra Ostapiuk ◽  
Ewa M. Urbanska
Keyword(s):  
Neurodegenerative Disorders ◽  
Kynurenic Acid

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.

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.

scholarly journals Novel Kynurenic Acid Analogues in the Treatment of Migraine and Neurodegenerative Disorders: Preclinical Studies and Pharmaceutical Design

2015 ◽  
Vol 21 (17) ◽  
pp. 2250-2258 ◽  
Author(s):  
Janos Tajti ◽  
Zsofia Majlath ◽  
Delia Szok ◽  
Anett Csati ◽  
Jozsef Toldi ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Kynurenic Acid ◽  
Preclinical Studies

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Polyphenol health effects on cardiovascular and neurodegenerative disorders: a meta-analysis

2019 ◽  
Author(s):  
Giorgia Spaggiari ◽  
Francesco Poti ◽  
Francesca Zimetti ◽  
Ilaria Zanotti ◽  
Daniele Santi
Keyword(s):  
Health Effects ◽  
Neurodegenerative Disorders ◽  
Meta Analysis

Preliminary outcomes in transcutaneous neuromuscular electrical stimulation use in patients with dysphagia

2018 ◽  
Vol 8 (31) ◽  
pp. 167-174
Author(s):  
Codrut Sarafoleanu ◽  
Raluca Enache
Keyword(s):  
Traumatic Brain Injury ◽  
Head And Neck Cancer ◽  
Electrical Stimulation ◽  
Neurodegenerative Disorders ◽  
Structural Changes ◽  
Congenital Abnormalities ◽  
Neuromuscular Electrical Stimulation ◽  
Therapy Options ◽  
Dysphagia Treatment ◽  
Risk Of Aspiration

Abstract Dysphagia is a common disorder associated with a large number of etiologies like aging, stroke, traumatic brain injury, head and neck cancer, neurodegenerative disorders, structural changes or congenital abnormalities. The type of the treatment and its results depend on the type, severity and the cause of dysphagia. The primary goal of dysphagia treatment is to improve the swallowing process and decrease the risk of aspiration. Along with the existing rehabilitation swallowing treatments, new adjunctive therapy options developed, one of them being the neuromuscular electrical stimulation (NMES). The authors present the principles of NMES, a small literature review about the results of this therapy and their experience in using transcutaneous NMES in dysphagia patients.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

2019 ◽  
Author(s):  
Jacob Porter ◽  
Oscar Vivas-Rodriguez ◽  
C. David Weaver ◽  
Eamonn Dickson ◽  
Abdulmohsen Alsafran ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Neurodegenerative Disorders ◽  
Channel Blocker ◽  
Optimal Combination ◽  
Channel Blockers ◽  
Enolate Alkylation ◽  
Cyp Inhibition ◽  
Alkylation Reactions ◽  
Metabolic Instability

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC<sub>50</sub>= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

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