The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders

Kandanearatchi, Apsara; Brew, Bruce J.

doi:10.1111/j.1742-4658.2012.08500.x

Cited by 47 publications

(48 citation statements)

References 69 publications

(107 reference statements)

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“…Katz et al, however, advocated that the role of kynurenine metabolites in immune response and inflammation may not be simple, 31,32 referring to the notion that depletion of tryptophan from T cells and/or tryptophan metabolites themselves might make T cells unable to trigger the appropriate immune reaction. 33 In the present study, kynurenine was associated with CRP, as were some metabolites of the kynurenine pathway in previous studies. 30 Given that inflammation is associated with muscle dysfunction 34, 35 and reduced functional capacity, 36 inflammation may be a common background both for higher kynurenine and impaired functional capacity observed in the present study.…”

Section: Potential Mechanismsmentioning

confidence: 68%

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

Konishi

Ebner

Springer

et al. 2017

Circ J

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Background: Kynurenine is a circulating metabolite from the essential amino acid tryptophan. Accelerated degradation of kynurenine in skeletal muscle has been reported to provide an anti-inflammatory effect. The aim of this study was to investigate the association between blood kynurenine and muscle mass/function in patients with heart failure (HF), in whom diseased muscle mass/ function plays a pathophysiological role. Methods and Results:Plasma kynurenine was assessed in 249 patients with HF (67±11 years, 21% women) and in 45 controls from the SICA-HF study. Kynurenine was higher in 173 HF patients with reduced ejection fraction (EF) and in 76 patients with preserved EF than controls (3.5±1.5, 3.4±1.3, and 2.4±1.1 μmol/L, P<0.001). In HF patients, kynurenine had an inverse association with handgrip strength (r=-0.26, P<0.01), peak oxygen consumption (r=-0.29, P<0.01), 6-min walk distance (r=-0.23, P<0.01), and had a positive association with kidney and liver function parameters. No correlation was observed between kynurenine and lean mass. On multivariable linear regression analysis, a significant association was noted between kynurenine and peak oxygen consumption even after adjustment for age, gender, BMI, and hemoglobin (β=-0.23, P<0.001). Patients with higher kynurenine were at higher risk of death (adjusted HR, 1.46 per 1 μmol/L, P<0.01). Conclusions:In stable HF patients, plasma kynurenine was inversely correlated with muscle strength and functional capacity as well as with liver and kidney function.

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Section: Potential Mechanismsmentioning

confidence: 68%

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

Konishi

Ebner

Springer

et al. 2017

Circ J

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“…The potential value of the kynurenine pathway for the development of new drugs acting in disorders such as these, in which a degree of neuronal damage is involved, has been discussed previously [90] In addition, the identification of a range of molecular targets such as GPR35, Finally, the parallel work that has developed since the early 1980s of the actions of kynurenines in the CNS and their effects in the immune system seem to be moving closer towards an integrated view of their interaction. That may in turn result in the development of compounds that can regulate changes in the processes of CNS neurotransmission directly, but which can also modify the development and progression of inflammatory reactions that increasingly seem to underlie chronic CNS disorders such as AD and HD, but may also be relevant to conditions such as multiple sclerosis (MS) [91] and infection-induced dementias [92]. This is certainly a pathway that is likely to become more intriguing in the future.…”

Section: Kynurenines and Drug Developmentmentioning

confidence: 99%

An expanding range of targets for kynurenine metabolites of tryptophan

Stone

Stoy

Darlington

2013

Trends in Pharmacological Sciences

303

207

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The kynurenine pathway of tryptophan metabolism accounts for most of the tryptophan that is not committed to protein synthesis and includes compounds active in the nervous and immune systems. Kynurenine acts on the aryl hydrocarbon receptor, affecting metabolism of xenobiotics and promoting carcinogenesis. Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDAR), but is also pro-oxidant, has immunomodulatory actions and promotes the formation of hyperphosphorylated tau proteins. Kynurenic acid blocks NMDARs and 7-homomeric nicotinic cholinoceptors but is also an agonist at the orphan G-protein-coupled receptor GPR35. 3-hydroxykynurenine and 3-hydroxyanthranilic acid have pronounced redox activity and regulate T cell function. Cinnabarinic acid can activate metabotropic glutamate receptors.The aim of this review is to highlight the increasing range of molecular targets for components of the kynurenine pathway, in both the nervous and immune systems, in relation to their relevance to disease and drug development. 3 The kynurenine pathwayApart from the tryptophan used in protein synthesis, most of this amino acid in mammals is oxidised along the kynurenine pathway. Only around 1% of tryptophan is used for the synthesis of 5-hydroxytrpytamine (5-HT). For many years, most compounds along the pathway ( Figure 1) were thought to have little biological activity until quinolinic acid was shown to be an agonist at glutamate receptors sensitive to NMDA [1] and kynurenic acid was found to be an antagonist at these and other ionotropic glutamate receptors [2]. These two compounds have been the focus of attention on the kynurenine pathway for over 30 years [3,4]. In parallel with work on the central nervous system (CNS), however, there has been growing interest in the role of kynurenines in the immune system, and the last few years have seen the identification of more molecular targets acted on by quinolinic acid, kynurenic acid or other components of the pathway. The key enzymes, indoleamine-2,3-dioxygenase (IDO) and kynurenine-3-monoxygenase (KMO) are also potential drug targets.The aim of this review is to highlight the increasing range of molecular targets now recognised in the nervous and immune systems in relation to their relevance to disease and drug development. Kynurenine metabolites and their receptors in disease Quinolinic acidIn addition to its ability to activate NMDARs selectively, quinolinic acid can generate reactive oxygen species (ROS). This activity can produce substantial oxidation of cellular lipids, especially in the presence of transition metal ions [5]. 4The axon-sparing neuronal loss produced by quinolinic acid in vivo may be due partly to formation of ROS [6] although it certainly also involves activation of NMDARs.Acting on human primary astrocytes, excitotoxic concentrations of quinolinic acid can also promote the expression and secretion of some of the more potent Kynurenic acidTwo early studies of the anti-epileptic actions of kynurenic acid independently reported that i...

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“…Despite our findings using these HD models, many studies have shown a strong correlation between IDO (indoleamine 2,3-dioxygenase, a key enzyme responsible for the production of kynurenine from tryptophan) activation, in situ-generated Quin neurotoxic levels, and the extent of neurodegeneration (Kandanearatchi and Brew, 2012;Plangar et al, 2012;Stone and Darlington, 2013;Vamos et al, 2009). The role of kynurenine catabolism in the regulation of the immune response is important, and this is difficult to evaluate in mouse models of HD.…”

Section: Discussionmentioning

confidence: 86%

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

Beaumont

Mrzljak

Dijkman³

et al. 2016

Experimental Neurology

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The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders

Cited by 47 publications

References 69 publications

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

An expanding range of targets for kynurenine metabolites of tryptophan

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

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The kynurenine pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders

Cited by 47 publications

References 69 publications

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure ― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure ― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

An expanding range of targets for kynurenine metabolites of tryptophan

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

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Product

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Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―

Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure　― Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) ―