Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism

Török, Nóra; Majláth, Zsófia; Fülöp, Ferenc; Toldi, József; Vécsei, László

doi:10.2174/1389200217666151222155043

Cited by 24 publications

(14 citation statements)

References 256 publications

(295 reference statements)

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“…Mitochondrial disturbances result in an energy deficit and the production of free radicals, which results in disruption of membrane potential and in oxidative stress. Free radicals may lead to protein misfolding or lipid peroxidation, thereby damaging neuronal cells [42].…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

et al. 2016

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Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

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Section: Discussionmentioning

confidence: 99%

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

et al. 2016

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“…In the pathology of different neurodegenerative disorders, the metabolism of endogenous TRY to kynurenic acid (KYNA) and/or quinolinic acid (QUIN) has received intensified attention because of its dual behavior of being neuroprotective or neurotoxic [71,72,73,74,75,76,77,78]. The steps of TRY metabolism are shown in Figure 1.…”

Section: Excitotoxicity In Multiple Sclerosismentioning

confidence: 99%

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Rajda

Pukoli

Bende

et al. 2017

IJMS

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future.

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“…KYNA binds to the GPR35 expressed in the glia, macrophages, and monocytes to reduce pro-inflammatory cytokine release in cell lines [105]. AA and its 5-hydroxylated metabolites may possess potential anti-inflammatory properties.…”

Section: Anti-inflammatory Kynureninesmentioning

confidence: 99%

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Tanaka

Toldi

Vécsei

2020

IJMS

Self Cite

198

197

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.

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Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism

Cited by 24 publications

References 256 publications

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

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