Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

Lugo-Huitrón, Rafael; Muñiz, Perla Ugalde; Pineda, Benjamín; Pedraza‐Chaverrí, José; Rı́os, Camilo; Cruz, Verónica Pérez-De La

doi:10.1155/2013/104024

Cited by 277 publications

(247 citation statements)

References 138 publications

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“…Modulatory effects on inflammation have been noted apart from the effects these metabolites have on receptor activity. For example, quinolinate is also produced by macrophages in the periphery in response to cytokine activation which, in turn upregulates other inflammatory mediators, such as MCP-1, a potent chemoattractant 33 , as well as enzymes involved in the conversion of tryptophan to quinolinate 31 . Therefore, quinolinate not only stimulates pro-inflammatory pathways, but also upregulates the enzymes which lead to its further production, in a forward-feed cycle.…”

Section: Discussionmentioning

confidence: 99%

Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults

et al. 2015

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Low versus high glycemic load (GL) diet patterns are inversely associated with obesity and chronic diseases such as cancer and cardiovascular disease. These associations persist beyond the protection afforded by increased fiber alone, representing an important gap in our understanding of the metabolic effects of GL. We conducted a randomized, controlled, crossover feeding trial of two 28-day diet periods of high and low GL. Using LC-MS, targeted metabolomics analysis of 155 metabolites was performed on plasma samples from 19 healthy adults aged 18-45 years. Fourteen metabolites differed significantly between diets (P<0.05), with kynurenate remaining significant after Bonferroni correction (P<4×10-4). Metabolites with the largest difference in abundance were kynurenate and trimethylamine-N-oxide (TMAO), both significantly higher after consumption of the low GL diet. Partial least squares-discriminant analysis showed clear separation between the two diets; however no specific pathway was identified in pathway analyses. We found significant differences in 14 plasma metabolites suggesting a differing metabolic response to low and high GL diets. Kynurenate is associated with reduced inflammation, and may be one mechanism through which protective effects of a low GL diet are manifested and warrants further evaluation. This trial was registered at clinicaltrials.gov as NCT00622661.

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Section: Discussionmentioning

confidence: 99%

Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults

et al. 2015

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“…Other toxic effects of QA through NMDA receptors have been observed, such as inflammatory events, energetic deficits, and behavioral and morphological alterations(42, 160, 174). The activity and toxicity of QA can change, depending on its levels.…”

Section: Kynurenine Pathwaymentioning

confidence: 99%

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

Liu²,

et al. 2015

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The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism, and it contributes to several fundamental biological processes. Trp is constitutively oxidized by tryptophan 2, 3-dioxygenase in liver cells. In other cell types, it is catalyzed by an alternative inducible indoleamine-pyrrole 2, 3-dioxygenase (IDO) under certain pathophysiological conditions, which consequently increases the formation of Kyn metabolites. IDO is up-regulated in response to inflammatory conditions as a novel marker of immune activation in early atherosclerosis. Besides, IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis. In particular, Kyn, 3-hydroxykynurenine, and quinolinic acid are positively associated with inflammation, oxidative stress (SOX), endothelial dysfunction, and carotid artery intima-media thickness values in end-stage renal disease patients. Moreover, IDO is a potential novel contributor to vessel relaxation and metabolism in systemic infections, which is also activated in acute severe heart attacks. The Kyn pathway plays a key role in the increased prevalence of cardiovascular disease by regulating inflammation, SOX, and immune activation.

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“…QUIN is antagonist of NMDA receptor and it has a high in vivo potency as an excitotoxin supporting involvement in the pathogenesis of a variety of human neurological diseases. The neurotoxicity of QUIN results from complex mechanisms including presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors and behavior [33]. We experimentally demonstrate that the disruption of the cytoskeleton, in particular, misregulation of the phosphorylation system associated with the IFs, is a target of QUIN toxicity in injected rat striatum, tissue slices and primary astrocytes and neurons in culture.…”

Section: Cytoskeleton Is a Target Of Quinolinic Acid Neurotoxicitymentioning

confidence: 94%

Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity

Zamoner¹,

Pessoa-Pureur²

2017

Cytoskeleton - Structure, Dynamics, Function and Disease

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In this chapter, we deal with the current knowledge and important results on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca 2+mediated mechanisms in developmental rat brain. We focus on the misregulation of the phosphorylating system associated with intermediate filament proteins of neural cells and its relevance to cell and tissue dysfunction. Taking into account our findings, we propose that intermediate-filament proteins are dynamic structures whose regulation is crucial for proper neural cell function. Given their relevance, they must be regulated in response to extracellular and intracellular signals. The complexity and connection between signaling pathways regulating intermediate-filament dynamics remain obscure. In this chapter, we get light into some kinase/phosphatase cascades downstream of membrane receptors disrupting the dynamics of intermediate filaments and its association with neural dysfunction. However, intermediate filaments do not act individually into the neural cells. Our results evidence the importance of misregulated cytoskeletal crosstalk in disrupting cytoskeletal dynamics and cell morphology underlying neural dysfunction in experimental conditions mimicking metabolic diseases and nongenomic actions of thyroid hormones and as an end point in the neurotoxicity of organic tellurium.

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Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

Cited by 277 publications

References 138 publications

Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults

Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity

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