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Urenjak, Jutta A., and Tihomir P. Obrenovitch. "Accumulation of quinolinic acid with euro-inflammation: does it mean excitotoxicity?" Thesis, Kluwer Academic, Plenum Publishers, New York, 2003. http://hdl.handle.net/10454/2833.
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Tutakhail, Abdulkarim. "Potential muscular doping effects of anti-depressants." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS513.
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Bien que l’effet psychotrope des antidépresseurs soit bien connu, afin de corriger les conséquences du stress et de renforcer la confiance en soi, de nombreux autres effets pharmacologiques, notamment périphériques, doivent encore être approfondis. Les antidépresseurs inhibiteurs de la recapture de la sérotonine (ISRS) peuvent avoir un effet bénéfique sur la performance physique en participant à une réparation et à une croissance plus rapides des muscles. Il a récemment été démontré que la sérotonine était impliquée dans la récupération de la force musculaire chez un modèle murin de myopathie de Duchenne (Gurel et al., 2015). Les antidépresseurs tels que les inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) sont largement utilisés pour traiter divers troubles de la santé mentale, tels que la dépression modérée à sévère et l’anxiété. Les deux symptômes contribuent à l’insomnie, à la perte d’appétit, au manque de motivation et à une fatigue physique accrue. Ces symptômes peuvent nuire aux performances physiques des athlètes, en particulier de ceux qui développent des habiletés et des techniques spécifiques à un sport, reçoivent des volumes d’entraînement plus importants à différentes intensités et participent à des compétitions plus fréquentes. Par conséquent, les athlètes peuvent utiliser des médicaments qui renforcent la motivation et / ou améliorent la condition physique générale en réduisant les symptômes dépressifs. L'utilisation d'antidépresseurs n'est pas encore interdite dans les sports d'élite. Des rapports récents sur le dopage associé aux ISRS montrent une tendance croissante de son utilisation chez les athlètes en bonne santé. La consommation d'antidépresseurs chez les athlètes a augmenté dans différents sports au cours de la dernière décennie, notamment les sports d'endurance.. Notre projet doit donc permettre de caractériser les conséquences d'un traitement chronique par ISRS sur les performances physiques chez la souris et de mettre en évidence le ou les mécanismes impliqués, en particulier la variation du shunt métabolique sérotonine / kynurénine, ainsi que les modifications de biomarqueurs, variations potentiellement utilisables chez l'homme dans la lutte contre le dopage.Nous aimerions élucider notre travail de recherche dans les articles suivants:Article 1: Nous avons étudié les effets de l'exercice et de la fluoxétine seuls ou en association avec un traitement prolongé à la fluoxétine (18 mg / kg / jour) et un exercice physique d'endurance (six semaines) chez la souris mâle BalbC / j, sur tapis roulant. Nous avons ensuite évalué l'activité neurocomportementale, les marqueurs musculaires du stress oxydatif et les modifications du métabolisme du tryptophane dans les tissus plasmatiques, musculaires et cérébraux des souris BalbC / J. En général, nous nous sommes concentrés sur la vitesse aérobie la plus élevée, le temps d’endurance jusqu’à l’épuisement, la force musculaire des membres antérieurs en saisissant un mesureur de force, des tests neurocomportementaux tels que le test en champ ouvert et élevé et le labyrinthe, l’activité enzymatique mitochondriale (activité du citrate synthase et du cytochrome C oxydase) dans le muscle gastrocnémien. , marqueur de stress oxydant tel que le test DHE (Dihydroéthidium) et DCF-DA (Dichlorofluorscine diacétate).Article 2: Nous avons étudié les effets de l’exercice et de la fluoxétine seule ou les effets combinés d’un traitement prolongé à la fluoxétine (18 mg / kg / jour) et d’un exercice d’endurance physique (six semaines) chez la souris mâle BalbC / j, sur tapis roulant<br>As much as the psychotropic effect of antidepressants is well known, correcting the consequences of stress and boosting self-confidence, so many other pharmacological effects, peripheral in particular, remain to be deepened. Serotonin reuptake inhibitor antidepressants (SSRIs) may have a beneficial effect on physical performance by participating in faster muscle repair and growth. It has recently been shown that serotonin was involved in the recovery of muscle strength in a mouse model of Duchenne myopathy (Gurel et al., 2015).Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely used to treat various mental health disorders, such as moderate-to-severe depression and anxiety. Both symptoms contribute to insomnia, loss of appetite, lack of motivation and increased physical fatigue. These symptoms can impair physical performances for athletes, more specifically for those who develop sport-specific skills and techniques, receive higher training volumes at various intensities, and participate in more frequent competitions. Therefore athletes may use drugs that enhance motivation and/or improve overall fitness by reducing depressive symptoms. The use of antidepressants is not yet forbidden in elite sports. Recent reports on doping associated with SSRIs show an increasing trend of its usage among healthy athletes. The antidepressants intake among athletes has increased in different sports over the last decade, especially endurance sports. The antidepressants Bupropion and Amineptine were removed from the list of banned substances.Our project must therefore make it possible to characterize the consequences of chronic treatment with SSRIs on the physical performance in mice and to highlight the mechanism (s) involved, in particular the variation of the serotonin / kynurenine metabolic shunt, as well as the modifications of biomarkers, potentially usable variations in humans in the fight against doping.We would like to elucidate our research work in the following articles:Article 1: We studied the effects of exercise and fluoxetine alone or in combination of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. Subsequently we evaluated neurobehavioral activity, muscle markers of oxidative stress, and changes in tryptophan metabolism in plasma, muscle and brain tissues in the BalbC/J mice. Generally we focused on the highest aerobic velocity, endurance time until exhaustion, forelimb muscle strength by gripping strength meter, neurobehavioral tests such as open field and elevated plus maze test, mitochondrial enzyme activity (Citrate synthase and cytochrome-C oxidase activity) in gastrocnemius muscle, oxidative stress marker such as DHE (Dihydroethidium) and DCF-DA (Dichlorofluorscine di-acetate)test.Article 2: We studied the effects of exercise and fluoxetine alone or combinative effects of long-term fluoxetine treatment (18mg/kg/day) and endurance physical exercise (six weeks) in male balbC/j mice, on animal treadmill. After the mentioned exercise protocol we focused on changes in tryptophan (TRP) metabolism in plasma, muscle and brain tissues in the BalbC/J mice. To confirm the metabolomic, we also studied the KP related enzyme related genes and proteins by the modern required materials and methods. We correlated the result of article1 with the metabolites level of kynurenine pathway of tryptophan metabolism. We studied the expression of transcriptor factor PGC1α level in muscle which is induced by physical exercise(Agudelo et al., 2014). PGC1α subsequently induce the expression of kynurenine aminotransferase 1 and 2 (KAT1 and KAT2) in skeletal muscles, which convert kynurenine (KYN) to kynurenic acid (KYNA). Conversion of kynurenine to kynurenic acid decrease the level of kynurenine and quinolinic acid an NMDA receptor agonist and a neurotoxic compound
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Pershing, Michelle. "Acute elevations in kynurenic acid result in cognitive inflexibility in an attentinal set-shfiting task via an alpha 7-mediated mechanism." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354032404.
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Milne, Gavin D. S. "Inhibition studies of kynurenine 3-monooxygenase." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4101.
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Kynurenine 3-monooxygenase (K3MO) lies on the kynurenine pathway, the major pathway for the catabolism of L-tryptophan. It converts kynurenine to 3-hydroxy kynurenine. Inhibition of K3MO is important in several neurological diseases and there is evidence that inhibition of K3MO could also be targeted for the prevention of multiple organ failure, secondary to acute pancreatitis. A structure activity relationship based upon the 1,2,4-oxadiazoles motif was carried out which revealed amide 207 as an inhibitor of P. fluorescens K3MO. Further structure activity relationships were developed based upon 207. This revealed 3,4-dichloro substitution in 235 and 245 as optimum for inhibition. Co-crystalisation of these inhibitors with P. fluorescens K3MO revealed their interactions with the enzyme. It also highlighted new, potential interactions between the inhibitors and K3MO. This led to the synthesis of 271 and 272, which were also potent inhibitors of K3MO. These amides were successfully co-crystalised with P. fluorescens K3MO. Further development of the amides followed, with amide 282 providing the most potent inhibitor of P. fluorescens K3MO to date (Kᵢ = 29.1 nM).
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Thevandavakkam, Mathuravani Aaditiyaa. "Deciphering the kynurenine-3-monooxygenase interactome." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10070.
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Kynurenine-3-monooxygenase (KMO) is a mitochondrial enzyme in the kynurenine pathway (KP) through which tryptophan is degraded to NAD+. The central KP is altered in neurodegenerative diseases and other CNS disorders. The causative role of KP metabolites has been particularly well studied in the neurodegenerative disorder Huntington’s disease (HD), a fatal adult onset condition inherited in an autosomal dominant manner. In HD, flux in the KP is perturbed such that neurotoxic metabolites (3-hydroxykynurenine and quinolinic acid) of the pathway are increased relative to a neuroprotective metabolite (kynurenic acid). KMO lies at a critical branching point in the KP such that inhibition of KMO activity ameliorates this metabolic perturbation. Consequently, several recent studies have found that KMO inhibition is protective in models of HD. These findings have widespread implications in treating several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease where the KP is implicated in pathogenesis. The focus of this project was to better understand the cellular role(s) and interactions of KMO. To this end, a novel membrane yeast two hybrid approach was established and optimised to identify protein interaction partners for outer mitochondrial membrane proteins. This approach was implemented to identify protein interaction partners of human KMO and its yeast orthologue Bna4, which were confirmed by biochemical approaches. Additionally, genetic interaction partners of BNA4 identified by systematic genetic screens were individually validated by classic genetic manipulations. Bioinformatic tools were then used to identify enriched interaction networks for KMO using this novel interaction data. These analyses suggested possible roles for KMO in many processes, including energy metabolism, cytoskeleton organisation and response to infection and inflammation, providing evidence that KMO plays roles in diverse cellular pathways in addition to the KP.
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Mackay, Gillian Moira. "Kynurenines in neurological disorders." Thesis, University of Glasgow, 2007. http://theses.gla.ac.uk/39/.
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The kynurenine pathway is thought to be involved in neurological disorders but its precise role and the mechanisms involved have yet to be established. Tryptophan can be metabolised via this pathway to produce the neurotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN), and the direct generators of reactive oxygen species, 3-hydroxykynurenine (3HKYN) and 3-hydroxyanthranilic acid (3HANA), as well as the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA). High performance liquid chromatography (HPLC) methods were successfully developed and validated for measuring tryptophan, kynurenine, KYNA, 3HANA and anthranilic acid (ANA) in blood samples, using absorbance and fluorescence detection. The method for determining 3HKYN using electrochemical detection was more problematic and was only used for tryptophan loaded samples and their respective baseline samples. Using HPLC, the concentrations of tryptophan, kynurenine, KYNA, 3HKYN and 3HANA were measured in the blood of Huntington's disease (HD) patients and patients with chronic brain injury, where the injury had occurred at least one year previously. QUIN was also determined for these patients using gas chromatography-mass spectrometry (GC-MS). In addition, the dynamics of the kynurenine pathway were investigated following oral tryptophan depletion and loading. In contrast to these chronic conditions, patients with acute stroke were also studied. The concentrations of tryptophan, kynurenine, KYNA, ANA and 3HANA were determined in the blood of the stroke patients, examining any changes in these concentrations during the two weeks after the stroke. The extent of inflammation and oxidative stress were also assessed for all patients, by measuring the levels of neopterin and the lipid peroxidation products, malondialdehyde and 4-hydroxynonenal. Patients with late stage HD showed abnormal tryptophan metabolism via the kynurenine pathway, together with increased inflammation and oxidative stress. Increased levels of kynurenine together with increased kynurenine: tryptophan (K:T) ratios, indicating greater indoleamine 2,3-dioxygenase (IDO) activity, were observed in blood samples from HD patients in comparison with healthy control subjects. In conjunction with this increased IDO activity, there was a decrease in the ratios of KYNA: kynurenine, suggesting decreased kynurenine aminotransferase (KAT) activity. Inflammation, which may be stimulating IDO activity, could also be decreasing KAT activity, suggested by negativecorrelations between the KYNA: kynurenine ratios and the inflammatory marker, neopterin. The inactivity of KAT suggests a small deficiency in KYNA over a long period of time which could cause a reduction in NMDA receptor antagonism, resulting in slow progressive excitotoxicity contributing to the neurodegeneration in HD. Low KYNA: kynurenine ratios were observed in baseline and tryptophan depleted samples, but after tryptophan loading, HD patients showed similar ratios compared with control subjects. This suggests that loading may be beneficial for HD patients, as more of the neuroprotectant, KYNA can potentially be produced. However, the results suggest that concentrations of the neurotoxin, QUIN, may also be increasing after tryptophan loading. Low concentrations of 3HKYN and 3HANA, with no change in QUIN levels, were also observed in the blood of HD patients. 3HANA levels continued to be decreased for the HD patients after loading. This may suggest degradation of 3HKYN and 3HANA by autoxidation producing reactive oxygen species which could contribute to the high levels of oxidative stress found in these patients. Tryptophan loading in healthy control subjects showed significant increases in the inflammatory marker, neopterin, and in the lipid peroxidation products. These results should be considered when tryptophan loading is used in psychiatric practice and in diets high in tryptophan, such as the Atkins diet. Patients with severe chronic brain injury showed similar alterations in kynurenine pathway metabolism as HD patients, at baseline and throughout the loading and depletion protocols. Although the brain injury had occurred at least one year previously, these patients showed persistent inflammation and oxidative stress, demonstrated by their increased levels of neopterin and lipid peroxidation products compared with healthy controls. In baseline blood samples, there were increased K:T ratios indicating greater IDO activity in the patients. Patients with chronic brain injury showed decreased concentrations of the neuroprotectant, KYNA, as well as low KAT activity, indicated by the decreased KYNA: kynurenine ratios. After tryptophan loading, K:T ratios decreased and the KYNA: kynurenine ratios increased in patients in comparison with controls, suggesting a reversal in the activities of the enzymes IDO and KAT. Similar levels of the inflammatory marker, neopterin, were observed in patients and controls after tryptophan loading. This suggests that these changes in IDO and KAT activities may be related to inflammation. As for the HD patients, patients with chronic brain injury showed lower levels of 3HKYN and 3HANA in their blood, with no change in QUIN levels. These metabolites may be undergoing autoxidation, producing reactive oxygen species which contribute to the ongoing oxidative stress in these patients.The kynurenine pathway was activated following an acute stroke, as indicated by the increased K:T ratios, suggesting greater IDO activity. Stroke patients also had raised levels of neopterin and lipid peroxidation products, indicating inflammation and oxidative stress. There were no changes in the blood concentrations of kynurenines, neopterin or lipid peroxidation products during the fourteen days after a stroke. Stroke patients had reduced levels of 3HANA in their blood, as observed for the HD and chronic brain injury patients. There were negative correlations between the concentration of 3HANA and the volume of the brain lesion, measured by computed tomography (CT) scan, demonstrating the importance of the decreased concentrations of 3HANA. In addition, there were increased levels of ANA in the blood of the stroke patients and the ratios of 3HANA: ANA also correlated with brain lesion volume. Another measurement which correlated with lesion volume was lipid peroxidation, suggesting that oxidative stress contributes to the extent of the brain damage after a stroke. This may suggest that the role of 3HANA in stroke is related to its autoxidation and the generation of reactive oxygen species. Increased concentrations of KYNA were observed in patients who died within three weeks of having a stroke. These high levels of KYNA may have been produced following excitotoxicity and the generation of free radicals, and may cause excessive NMDA receptor blockade or reduced mitochondrial adenosine triphosphate (ATP) synthesis, thus contributing to cell death. The kynurenine pathway was activated and showed abnormal metabolism in all the patient groups, suggesting a potential role for these metabolites in neuronal dysfunction in HD, chronic brain injury and acute stroke. Further work is required to elucidate the role of tryptophan metabolites and whether they may have a direct contribution to neuronal damage in neurological disorders.
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Bell, Helen Barbara. "Characterisation of the active site of kynurenine 3-monooxygenase." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/20397.
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Kynurenine 3-monooxygenase (KMO) is a flavoprotein which has been implicated in Huntington’s disease, Alzheimer’s disease and acute pancreatitis. Recently there has been important research published about this enzyme including the structure of a truncated Saccharomyces cerevisiae KMO enzyme and KMO inhibition studies in animal models of disease. In previous work from this research group the complete Pseudomonas fluorescens KMO enzyme has been successfully crystallised both with and without the substrate, L-kynurenine, from which significant insights were gained into function and the potential role of domain movement. To examine substrate binding in KMO and to consolidate previous structural studies, key residues in the active site have been investigated using site directed mutagenesis, crystallography and kinetic analysis using steady-state techniques. This analysis has identified the interactions between the enzyme and the substrate and provides a basis for inhibitor design. The residues implicated in substrate binding are N369, Y404 and R84. For N369 and Y404, minor changes to the amino acid in the mutations N369S and Y404F were shown to cause a decrease in binding affinity of the substrate but the enzyme remained active. For the mutations Y404A and R84K enzyme activity was significantly affected. Crystal structures of N369S, Y404F and R84K were also obtained. Another residue in the active site studied was H320 which is the only amino acid to differ in the active sites of the human and Pseudomonas fluorescens enzymes. This residue was therefore of interest to determine whether the bacterial enzyme used in this work is likely to be a good model for the human enzyme, which has not yet been successfully isolated in significant quantities for in vitro research. Modifying this residue to obtain H320F KMO revealed that this residue does not have a significant role in substrate binding. Potent inhibitor molecules have been studied with this enzyme and shown in kinetic assays to have nanomolar Ki values. These inhibitors are the most potent inhibitors studied with Pseudomonas fluorescens to date and continue previous inhibitor studies carried out with this enzyme. This group of inhibitors contain different substituents in the part of the molecule shown to bind closest to the C-terminal domain of the protein. These novel inhibitors do not allow the flavin to be reduced by NADPH (which results in unwanted peroxide production) unlike a number of previously studied molecules and therefore have the potential to be clinically useful. This research therefore answers many questions about this enzyme, in particular about the role of particular residues in the active site, substrate recognition and inhibition of this important drug target.
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Owe-Young, Robert School of Medicine UNSW. "Kynurenine pathway metabolism at the blood-brain barrier." Awarded by:University of New South Wales. School of Medicine, 2006. http://handle.unsw.edu.au/1959.4/26183.
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A major product of HIV-infected and cytokine-stimulated monocytic-lineage cells is quinolinic acid (QUIN), a neurotoxic metabolite of the kynurenine pathway (KP) of L-tryptophan (L-Trp) metabolism. Despite the large number of neurotoxins found in HIV patients with AIDS Dementia Complex (ADC), only QUIN correlates with both the presence and severity of ADC. With treatment, cerebrospinal fluid (CSF) QUIN concentrations decrease proportionate to the degree of clinical and neuropsychological improvement. As endothelial cells (EC) of the blood-brain barrier (BBB) are the first brain-associated cell that a bloodborne pathogen would encounter, this project examined the BBB response to KP metabolites, as these are implicated in damage of the CNS associated with ADC. Using RT-PCR and HPLC/gas chromatographymass spectrometry (GC-MS), I found that cultured primary human BBB EC and pericytes constitutively expressed the KP. EC synthesised kynurenic acid (KA) constitutively, and after immune activation, kynurenine (KYN). Pericytes produced small amounts of picolinic acid and after immune activation, KYN. An SV40-transformed BBB EC showed no KP expression. By contrast, human umbilical vein EC only expressed low levels of KA after immune activation, however human dermal microvascular EC showed a similar constitutive and inducible KP to that in BBB EC. As T cells are central to primary HIV infection, I also examined KP expression in two CD4+ and one CD4- cell lines, but none showed either constitutive or inducible KP expression. I next examined how QUIN might interact with BBB EC. There was no binding of 3H-QUIN to cultured primary human BBB EC, however a biologically relevant concentration of QUIN induced changes in gene expression which adversely affected EC function, possibly mediated by lipid peroxidation and oxidative stress. The upregulated genes were of the heat shock protein family, and the downregulated genes were associated with regulation of cell adhesion, tight junction and cytoskeletal stability, metalloproteinase (MMP) regulation, apoptosis and G protein signaling. Immunofluorescence showed that QUIN induced morphological changes in BBB EC consistent with the changes in gene expression. Gelatin zymography showed that this was not mediated by MMPs, as constitutive MMP expression was unchanged. These data provide strong evidence for QUIN directly damaging the BBB in the context of HIV infection.
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Taylor, Mark Robert Duncan. "High-resolution structural studies of kynurenine 3-monooxygenase." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28913.
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The kynurenine pathway produces NAD+ from L-tryptophan. Metabolites known as the kynurenines are produced within the pathway. The effects of the kynurenines have been associated with a number of diseases including cancer, Alzheimer’s disease, Huntington’s disease, and acute pancreatitis. Kynurenine monooxygenase (KMO) is an enzyme that catalyses the conversion of L-kynurenine to 3-hydroxy-L-kynurenine, the downstream product of which is the neurotoxic quinolinic acid. L-kynurenine is positioned at a branching point within the pathway. Metabolism via KMO leads to quinolinic acid production whereas conversion via kynurenine aminotransferase (KAT) produces the neuroprotective kynurenic acid. Inhibition of KMO leads to an increase in kynurenic acid concentration. This has also been shown to ameliorate the symptoms of neurological diseases in a number of animal models as well as to protect against multiple organ dysfunction caused by acute pancreatitis in rodent models. These findings present KMO as a promising drug target. Due to the hydrophobic nature of human KMO (hKMO) it has been necessary to utilise other forms of KMO as models. Past studies have produced crystal structures of a truncated Saccharomyces cerevisiae KMO and of Pseudomonas fluorescens KMO (PfKMO). Previous work in this research group has resulted in the structure of variants of PfKMO bound to either inhibitor molecules or substrate. These structures identified residues involved in substrate binding and the presence of a highly mobile section of the C-terminus, giving rise to open and closed conformations. It was surmised the movement of the C-terminus was dependent upon the presence of substrate and an interactive network between the C-terminus and the rest of the protein. Using improved crystallising conditions high-resolution structures of PfKMO have been produced that allow for further study of residues involved in substrate binding and the interactive network within the C-terminus. The mutants R84K and Y404F showed severely decreased enzyme activity. Crystal structures of these proteins showed disrupted interactions between substrate and active site. These findings underline the importance of residues R84 and Y404 in substrate binding. An H320F mutation gives an analogous active site to hKMO. Crystallographic and kinetic study of this mutant proved very similar to PfKMO, supporting the use of PfKMO as a model for hKMO. Throughout the work each structure had a P21221 space group with two molecules in the asymmetric unit. The presence of an open and closed molecule within each structure, including substrate-free molecules refuted the connection between C-terminus and substrate. R386K and E372T mutations were separately introduced in order to interrupt the interactive network. The presence of both open and closed conformations in the structures of R386K and E372T refutes the necessity for the interactive network in C-terminus movement. The data analysed throughout the project suggest simple mobility and thermal motion as the cause of the movement of the C-terminus. This work, in conjunction with kinetic data from the thesis of Helen Bell, presents structural data to characterise the role of binding residues within the active site of KMO as well as the mechanistic role of the C-terminus. It also highlights the importance of certain binding residues and countered the previously held hypotheses surrounding the significance of the C-terminus. The mechanistic role of the C-terminus therefore remains unclear and requires further study.
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Wilkinson, Martin. "Structural dynamics and ligand binding in kynurenine-3-monooxygenase." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/7965.
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Kynurenine 3-monooxygenase is a FAD-dependent aromatic hydroxylase (FAH) which is a widely suggested therapeutic target for controlling the balance of bioactive metabolite levels produced by the mammalian kynurenine pathway (KP). Prior to starting this work no structural information was known for the enzyme, with studies of the human form complicated by the presence of a C-terminal transmembrane helix. The bacterial Pseudomonas fluorescens enzyme (PfKMO) lacks the transmembrane region and has been previously characterised by Crozier-Reabe and Moran [1, 2]. Therefore PfKMO, which shares 32 % sequence identity with the human enzyme, was selected as a target for structure solution. Initial substrate bound PfKMO crystals showed poor X-ray diffraction. Subsequent growth optimisation and the generation of a C252S/C461S PfKMO mutant (dm2) yielded crystals suitable for structure solution. Selenomethioninelabelled substrate bound dm2 crystals were used to solve the first structure to a resolution of 3.40 Å. With just one protein molecule per asymmetric unit, a high solvent content was responsible for the poor diffraction properties of this crystal form. The overall fold resembled that of other FAH enzymes with a Rossmann-fold based FADbinding domain above a buried substrate binding pocket. Interestingly PfKMO possesses an additional, novel C-terminal domain that caps the back of the substrate-binding pocket on the opposite side to the flavin. Residues proposed to be involved in substrate binding were identified and shown to be highly conserved among mammalian KMO sequences. Subsequently single crystals of substrate-free dm2 PfKMO were obtained and showed significantly stronger diffraction due to new lattice packing in an orthorhombic space group bearing four molecules per asymmetric unit. The structure was solved to a resolution of 2.26 Å and revealed a clear conformational change of the novel C-terminal domain. This movement opens a potential route of substrate/product exchange between bulk solvent and the active site. The investigation of a set of C-terminal mutants further explored the relevance and mechanics of the conformational change. In addition the presence of chloride ions in the substrate-free crystal growth solution caused a small number of localised subtle alterations to the structure, with a potential chloride binding site identified adjacent to the flavin cofactor. This may have relevance for the observed inhibition of PfKMO activity by monovalent anions – a feature widely common to FAH enzymes [3]. The first discovered KMO inhibitors were analogues of the substrate L-Kyn, however one such compound (m-NBA) was recently shown to instigate uncoupled NADPH oxidation leading to the release of cytotoxic hydrogen peroxide [1]. A set of substrate analogues were tested and characterised for inhibition of PfKMO. The picture was shown to be complex as some substrate analogues completely inhibited the enzyme whilst the binding of some still stimulated low-levels of NADPH oxidation. Crystallographic studies with m-NBA and 3,4-dichlorobenzoylalanine (3,4-CBA) bound revealed indistinguishable structures from that of substrate-bound PfKMO. These studies suggest that the analogue 3,4CBA is a potent PfKMO inhibitor whose therapeutic potential may be re-visited. The previous most potent KMO inhibitor whose structure was not analogous to the substrate was Ro 61-8048 [4], which unfortunately did not pass pre-clinical safety tests. A novel series of 1,2,4-oxadiazole amides based on the structure of Ro 61-8048 was created by Gavin Milne (PhD, University of St Andrews) and tested on PfKMO. Rounds of refinement led to the discovery and refinement of low nanomolar competitive inhibitors of the bacterial enzyme. PfKMO was co-crystallised with each of the four most potent compounds forming a third different lattice arrangement, which yielded structures to resolutions of 2.15-2.40 Å. The structures displayed conformational changes resembling the substrate-free fold possibly caused by displacement of a crucial substrate-binding residue, R84. Overall the wealth of structural data obtained may be transferable to predictions about the structural features of human KMO and to the rational design of therapeutic inhibitors. The potent novel inhibitors tested may additionally present a new exciting development for the therapeutic inhibition of human KMO.
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Skouras, Christos. "Kynurenine metabolism and organ dysfunction in human acute pancreatitis." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28898.
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BACKGROUND: Acute pancreatitis (AP) is a sterile initiator of systemic inflammation that can trigger multiple organ dysfunction syndrome (MODS). In the acute phase of AP, the kynurenine pathway of tryptophan metabolism plays an important role in the genesis of AP-MODS in experimental animal models, but it is unknown whether the pathway is activated in human AP. Human data are required to support the rationale for kynurenine 3- monooxygenase (KMO) inhibition as a treatment for AP-MODS and reinforce the translational potential. Additionally, as respiratory dysfunction is frequent in severe AP, the role of lung ultrasonography in severity stratification deserves investigation. Furthermore, the effect of AP-MODS on long-term survival is unknown. OBJECTIVES: My objectives were to: 1) Define the temporal and quantitative relationship of kynurenine metabolites with the onset and severity of APMODS, 2) Investigate the value of lung ultrasonography in the early diagnosis of respiratory dysfunction in human AP-MODS, and 3) Examine whether early AP-MODS impacts on long-term survival. METHODS: 1) A prospective, observational, clinical experimental medicine study titled “Inflammation, Metabolism, and Organ Failure in Acute Pancreatitis” (IMOFAP) was performed. For 90 days, consecutive patients with a potential diagnosis of AP were recruited and venous blood was sampled at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. Kynurenine metabolite concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and analysed in the context of clinical data, disease severity indices, and cytokine profiles. 2) In a nested cohort within IMOFAP, 41 participants underwent lung ultrasonography to evaluate whether this imaging modality can detect respiratory dysfunction in AP. 3) Survival data for a prospectively maintained database of patients with AP was analysed after accounting for in-hospital deaths. RESULTS: 1) During the IMOFAP study, 79 patients were recruited with an elevated serum amylase, of which 57 patients met the diagnostic criteria for AP; 9 had severe disease. Temporal profiling revealed early tryptophan depletion and contemporaneous elevation of plasma concentrations of 3- hydroxykynurenine, which paralleled systemic inflammation and AP severity. 2) Lung ultrasonography findings correlated with respiratory dysfunction. 3) 694 patients were followed up for a median of 8.8 years. AP-MODS conferred a deleterious effect on overall survival which persisted after the exclusion of inhospital deaths (10.0 years, 95% C.I. = 9.4-10.6 years) compared to AP without MODS (11.6 years, 95% C.I. = 11.2-11.9 years; P = 0.001). This effect was independent of age. CONCLUSIONS: In the acute phase of AP, metabolic flux through KMO is elevated and proportionate to AP severity. Lung ultrasonography may be a useful technique for evaluating AP-MODS. AP-MODS is an independent predictor of long-term mortality. Together, this work reinforces the rationale for investigating early phase KMO inhibition as a therapeutic strategy in humans.
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Kolodziej, Lukasz. "An investigation of the kynurenine pathway in experimental arthritis." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9641.
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The kynurenine pathway is a catabolic biochemical pathway responsible for degradation of tryptophan, an essential amino acid. As a consequence, biologically active molecules, kynurenines, are produced. These chemical entities can influence immune responses. Previously, it has been shown that pharmacological inhibition of the initial step on the pathway increases the severity of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. In contrast, treatment with kynurenine, a major by product of tryptophan degradation, effectively ameliorated the disease. This project was based around the hypothesis that tryptophan metabolism via the kynurenine pathway represents an endogenous regulatory mechanism that is activated in response to inflammation. To test this hypothesis, I carried out a comprehensive analysis of the kynurenine pathway in the immune system in CIA as well as in the liver or kidneys, organs in which kynurenine pathway is the most active under normal conditions. In this study, the endogenous activity of the kynurenine pathway in the immune system (lymph nodes and spleen), inflamed paws, liver, and kidneys was monitored during the induction phase of CIA (day 14 after immunisation) and during the period of disease resolution (day 10 after disease onset). In addition, the concentration of tryptophan, kynurenine and its selected catabolites anthranilic acid (AA) and 3-hydroxyanthranilic acid (3-HAA) was determined in the sera. All results were compared with naive tissues.Increased expression of all enzymes along the kynurenine pathway was observed locally in draining lymph nodes during the pre-arthritic phase of arthritis and this was accompanied by reduced levels of tryptophan. In contrast, during the resolution phase of arthritis not only was there decreased tryptophan concentration, but also there was an accumulation of the downstream tryptophan metabolites, kynurenine, AA, and 3-HAA in lymph nodes. In addition, the accumulation of kynurenine and its downstream metabolites observed during the resolution of arthritis was accompanied by reduced expression of enzymes involved in kynurenine catabolism (kynureninase, kynurenine 3-monooxygenase, and 3-hydroxyanthranilate 3,4 dioxygenase) towards the levels found in naïve mice. These findings provide for the first time evidence of an association between resolution of arthritis and the local accumulation of kynurenines in lymph nodes. However, in the paws and spleens of mice with CIA, there was no evidence of activation of the kynurenine pathway. Surprisingly, however, kynurenine catabolism was increased in the kidneys and liver during CIA which may explain why in sera from mice with CIA, the tryptophan concentration was not changed, whereas levels of kynurenine, AA, and 3-HAA actually decreased, despite the increased levels found in lymph nodes at the same time points. Based on these findings I assessed the potential therapeutic effect of exogenous administration of AA and 3-HAA in mice with established CIA and in order to facilitate this study I established a novel method of assessment of bone integrity based on 3-dimensional imaging using micro-computed tomography. Using in vivo observations, micro-computed tomography and histological sectioning with hematoxylin and eosin staining, I showed that neither AA nor 3-HAA treatment was effective in established CIA. However, treatment with etanercept, a potent inhibitor of TNF, profoundly reduced the severity of bone and cartilage damage. I also confirmed previous findings that tranilast, a derivative of 3-HAA which exhibits kynurenine-like activity and has a longer half-life than naturally occurring tryptophan metabolite, was effective in established CIA. Thus, taken together, activation of the kynurenine pathway in the lymph nodes may constitute a fine tuning mechanism involved in resolution of inflammation. However, exogenous administration of naturally occurring kynurenines is unlikely to be an effective therapeutic strategy to reduce inflammation in arthritis, possibly because of their rapid clearance from the circulation.
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Swaih, Aisha Mahmod O. "Functional and localization studies of human kynurenine 3-monooxygenase." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37835.
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Kynurenine 3-monooxygensae (KMO) is an outer mitochondrial membrane protein which plays a critical regulatory role in the kynurenine pathway (KP), catalysing the production of 3-hydroxykynurenine (3-HK). Increased KMO activity likely contributes to the excitotoxicity seen in neurodegenerative disorders by elevating the levels of the neurotoxic KP metabolites 3-HK and quinolinic acid. Studies employing models of Huntington’s disease (HD) have shown that inhibition of KMO is neuroprotective, making KMO a potential therapeutic target for this disorder. This study interrogates the subcellular localisation of human KMO and dissects the interaction between KMO and the huntingtin (HTT) protein, mutations in which cause HD. Confocal microscopy based co-localisation studies of KMO demonstrated that full length KMO (flKMO) was exclusively localised to the mitochondria when expressed in HEK293T cells. Notably, deleting a C-terminal portion of flKMO which contains a putative transmembrane domain mis-localised the remaining protein (tKMO) to other cellular compartments. Localization of flKMO to the outer mitochondrial membrane was further confirmed via transmission electron microscopy. To study potential interactions between flKMO and HTT in living cells, bimolecular fluorescence complementation (BiFC) assay was utilised, which is based upon reconstitution of split fluorescence proteins. The BiFC approach allowed visualisation and quantification of flKMO interaction with both WT HTT and soluble mHTT fragments at the mitochondria. The strength of this interaction is inversely correlated to the length of the HTT polyglutamine expansion. Increased mitochondrial sub-cellular localisation of BiFC HTT constructs was confirmed via microscopy. tKMO however did not interact with HTT via the BiFC system, indicating that the C-terminal region of flKMO is important for both mitochondrial localisation and protein interaction. In total, these data suggest that flKMO-HTT interactions at the mitochondria may be biologically significant and could play a role in regulating KMO activity, and that in HD this regulatory process is impaired.
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Chen, Yiquan Medical Sciences Faculty of Medicine UNSW. "The involvement of the Kynurenine pathway in amyotrophic lateral sclerosis." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43774.
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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unclear aetiology, although the general consensus is of a multifactorial disease. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous metal chelator. The first and inducible enzyme is indoleamine 2,3-dioxygenase (IDO). As the extent of the involvement of the KP in ALS is unknown, the main aim of this thesis was to attempt to answer that question. The techniques used in this work include HPLC, GC/MS, RT-PCR, immunohistochemistry and immunocyctochemsitry. The main findings of this project are: (1) the complete KP is present in the mouse motor neuron cell line, NSC-34; (2) QUIN toxicity on NSC-34 cells may be ameliorated through the administration of NMDA antagonists, neuroprotective kynurenines, kynurenine inhibitor and QUIN monoclonal antibody; (3) in ALS patients, QUIN CSF and serum levels are significantly elevated, while PIC serum levels are significantly reduced; (4) ALS brain and spinal cord tissue show extensive microglia activation and positive immunoreactivity IDO and QUIN in spinal motor neurons and Betz cells in the motor cortex; and (5) kynurenine pathway inhibitor and analogue, R061-8048 and tranilast, are able to prolong the survival in the G93A SOD1 ALS transgenic mouse model. In conclusion, this study provide the first strong evidence for the involvement of the KP in ALS, and these data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which is amenable to KP analogue and inhibitor in ALS transgenic mice.
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Zaher, Sarah Samir Abd-Elazim. "IDO and kynurenines in corneal allograft rejection." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9127.
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Transplantation is currently the only form of treatment for many blinding diseases caused by opacity of the cornea. Corneal graft rejection is the single most important reason for corneal graft failure and survival rates have not improved over the decades. Alternative investigative interventions have been studied in experimental models of corneal transplantation for many years. IDO catabolises tryptophan and as a consequence of this and the production of tryptophan catabolites (kynurenines) downregulates T cell responses. Overexpression of IDO by virus-mediated cDNA transfer to donor cornea ex vivo prior to transplantation prolongs graft survival. As the overall objective of this project was to develop IDO or kynurenines as potential therapeutic targets for preventing corneal allograft rejection, the first part of this thesis examined potential methods of upregulation of IDO expression in the cornea, concentrating on the effect of UVB exposure on IDO expression. Upregulation of IDO at the mRNA level but not the protein or functional level was demonstrated in response to UVB exposure. The second part of this thesis examined whether kynurenines could mimic the effect of IDO in prolonging corneal graft survival. It was demonstrated that the effect of IDO overexpression in delaying graft rejection could be replicated by both the systemic and local administration of kynurenines. Furthermore the potential mechanism of action of this observed effect was investigated at the in vitro and in vivo levels with kynurenines demonstrating selective T cell cytotoxicity in vitro as well as local and systemic depletion of lymphocyte counts after both local and systemic administration of kynurenines respectively. Given the potential of using kynurenines as a therapeutic strategy in patients, the third part of this thesis examined the effect of a commercially available tryptophan metabolite- Tranilast- on allograft survival. Significant prolongation in graft survival was observed and the potential mechanisms of action of this drug were analysed. Tranilast inhibited T cell proliferation through cell cycle arrest as a result of upregulation of p21 and p15 (cell cycle inhibitors) and downregulation of Cyclin E. An associated reduction in IL-2 production was also observed allowing us to characterise a novel mechanism for Tranilast induced CD4+ T cell anergy. Further to emerging evidence indicating a role for the aryl-hydrocarbon receptor (AhR) in CD4 T cell differentiation and a tryptophan photo-product as a ligand of the AhR, the fourth part of this thesis examined the potential of kynurenines (3- hydroxykynurenine-3HK) as well as Tranilast as agonists of the AhR. 3HK and Tranilast were found to activate the AhR and the downstream signalling pathway. Collectively, the data represented in this thesis helps to explain the effects of IDO and kynurenines in prolonging corneal allograft survival and helps to shed light on the direct immunoregulatory mechanism of IDO and kynurenines. The identification of a commercially available drug effective in prolonging corneal allograft survival may prove a useful adjunct or alternative to topical corticosteroids that can be transferred from the laboratory to clinical practice.
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Miranda, Allan F. "Modulation of quinolinic acid-induced excitotoxicity by endogenous kynurenine pathway intermediates." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq22484.pdf.
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Parker, Nicole Renee. "The role of kynurenine and UV light in lens protein modification." Access electronically, 2005. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20060720.111305/index.html.
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Thesis (Ph.D.)--University of Wollongong, 2005.<br>Typescript. EMBARGOED - This thesis is subject to a 12 month embargo (07/03/06 to 07/03/07) and may only be viewed and copied with the permission of the author. For further information please Contact the Archivist. Includes bibliographical references: leaf 236-266.
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Khalil, Omari S. "Effects on brain development of prenatal inhibition of Kynurenine-3-Monooxygenase." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5075/.
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Much is known about the disease pathology related to schizophrenia, however, little is known with regards to its aetiology. Recent evidences suggest a neurodevelopmental hypothesis for schizophrenia where environmental factors including: infection, stress and malnutrition, can adversely affect the pregnant mother thereby elevating the risk for schizophrenia developing in the offspring during adulthood (Meyer et al., 2008d; Meyer and Feldon, 2009; 2012; Forrest et al., 2012; Meyer, 2013). Since a variety of viral and bacterial infections in animal models have demonstrated to increase the risk in schizophrenia, it is proposed that factors common to the immune response may mediate this link. While many laboratories have reported several behavioural abnormalities following maternal immune activation, we sought to examine molecular changes following poly(I:C) exposure, a synthetic viral mimetic, in the pregnant mother and assessed a range of protein markers with known developmental roles, since an appreciable understanding of the molecular alterations taking place would permit suitable therapies to follow. Interestingly, poly(I:C) was able to induce a range of changes resembling those observed during schizophrenia, where the major NMDA receptor subunit GluN1 and α-Synuclein was reduced in postnatal day 21 animals born to mothers treated with poly(I:C) during gestation days 14, 16 and 18. Furthermore, these changes suggest a mechanism by which maternal immune activation may lead to the subsequent emergence of schizophrenia. Another aspect of this work examined the role of the kynurenine pathway on brain development. There is increasing evidence suggesting the involvement of the kynurenine pathway, a biochemical pathway responsible for the oxidative metabolism of tryptophan, in the disease pathology of schizophrenia, including neurodegenerative disorders such as Parkinson’s, Alzheimer’s and Huntington’s disease (Giorgini et al., 2005; Ting et al., 2009; Bonda et al., 2010). Since immune activation induces the activation of the kynurenine pathway, it was hypothesised that alterations in central kynurenine concentrations during development may be involved in mediating the subsequent increased risk for schizophrenia (Forrest et al., 2013, Khalil et al., 2013, 2014). As very little is known about the physiological activity of the kynurenine pathway during development, we sought to examine the potential consequence of disrupting this pathway and examining its effects upon brain development. Therefore, a kynurenine monooxygenase inhibitor, Ro61-8048, was administered to pregnant rats during gestation day 14, 16, and 18, that would inhibit the synthesis of the neurotoxic metabolite quinolinic acid, while redirecting the pathway to increase the neuroprotectant kynurenic acid. Brain development was assessed by examining changes in protein expression of markers intimately involved in synaptic transmitter release machinery, neurogenesis and many aspects of neuronal development. Interestingly, we found the kynurenine pathway is highly active during brain development, and induces a variety of changes in protein markers that may be involved in precipitating a range of neuronal and cognitive deficits. While Ro61-8048 induced no changes in the embryo brains at 5 and 24 h following treatment, delayed changes were seen in postnatal day 21 animals displaying a decrease in RhoB expression as examined in the western blots. Since the full blow symptoms of schizophrenia become apparent during early adulthood, we sought to examine any changes in protein expression in postnatal day 60 animals in regions of the cortex, hippocampus, midbrain and cerebellum. Interestingly, profound alterations were seen in doublecortin and the netrin receptors responsible for axonal guidance. Perhaps the most striking protein change in the postnatal day 60 animals is the significant alteration induced in the expression of disrupted in schizophrenia (DISC)-1, a protein strongly linked with schizophrenia. Glutamate function was assessed as indicated by the density of glutamate transporters, VGLUT-1 and VGLUT-2, in the CA1 region of the hippocampus of postnatal day 60 animals using immunocytochemistry. While the relative density of glutamate transporters were substantially increased, there were no changes in the GABA transporters, indicating that while GABA transmission remained the same, glutamate function may have increased in the absence of an increase in synaptic connections. Spine densities of pyramidal neurons in the hippocampus were also examined, using the golgi-impregnation method, to reveal a significant loss in spines of the apical and basal dendrites, consistent with reports in schizophrenia. To conclude, the kynurenine pathway is highly active during development, and alterations in central kynurenines during pregnancy, as induced by environmental factors such as stress and infection, may be involved in the subsequent emergence of neurodevelopmental disorders.
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Kubo, Hisako. "Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225521.
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Bipath, Priyesh. "Tryptophan and the kynurenine pathway in chronic renal failure patients on dialysis." Diss., Pretoria : [s.n.], 2008. http://upetd.up.ac.za/thesis/available/etd-10212008-135418.
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Prescott, Christina Rapp. "Dual effects of kynurenic acid on AMPA receptors /." Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Neuroscience) -- University of Colorado, 2005.<br>Typescript. Includes bibliographical references (leaves 116-128). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Pisar, Mazura Md. "The role of kynurenine metabolism in the development of the central nervous system." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5550/.
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Prenatal exposure to maternal infection has been thought as a major risk factor for neurodevelopmental brain damage and thus contributes to the pathophysiology of neurodegenerative diseases including schizophrenia and autism. The mechanisms of aberrant neurodevelopmental processes on the offspring, in which primary cerebral insults occur during early brain development, are not fully understood. In the present investigation, maternal infection was modelled in timed-pregnant rats at embryonic day (E) 14, 16 and 18 by administering intraperitoneal injections of polyriboinosinic-polyribocytidilic acid,poly(I:C), a viral mimetic double stranded RNA complex which activates Toll-Like-Receptor-3 (TLR-3). The aim was to examine the impact of maternal inflammatory response on the regulation of expression of neurodevelopmental proteins that play important roles in many neurodevelopment aspects, including maintenance of synaptic plasticity, intracellular signalling and neurogenesis which may be relevant in cognitive and behavioural functions. An examination of embryo brains 5 h after maternal poly(I:C) showed significant differences in expression of the NMDA receptor NR2 subunits. The expression of NR2A subunits was reduced, whereas infection induced during pregnancy enhanced NR2B subunit expression. Expression levels of both subunits at postnatal day 21 (P21) were not affected by prenatal poly(I:C) exposure. In utero viral challenge led to significant changes among neurogenesis factor only at P21. In the fetal brain, acute poly(I:C) exposure had no effect on the expression of SHH, PCNA and also SOX2 proteins. However, when poly(I:C) was administered during mid and late gestation in the rodent model, long term effects of prenatal viral challenge on survival and maintenance of cell in the brain as indicated by the expression of SOX2 and SHH was clearly demonstrable. Expression of SOX2 level was increased,while SHH was significantly decreased, suggesting possible increase in the number of cells and changes in the rate of differentiation, respectively. The results demonstrate that poly(I:C) challenge in pregnant dams results in selective molecular changes in the brain, with transient alteration in the levels of NMDA receptor subunit NR2A and NR2B in the foetal brain, and also affecting molecules associated with cell genesis processes at later stages of developmental age of offspring. On the other hand, recent pharmacological interest in kynurenines with respect to CNS diseases has mainly focussed on two neuroactive molecules: quinolinic acid (QUIN) and kynurenic acid (KYNA). Manipulation of the kynurenine pathway and its neuroactive metabolites has been associated with N-methyl-D-aspartate (NMDA) receptor neurotoxicity and dysfunction which linked to the development of various neurological disorders. An early developmental event has been proposed to precipitate alterations in the NMDA receptor function. In this respect, early development during the gestational period of rats is most suitable for investigating the modulating effect of kynurenine pathway inhibition by compound Ro61-8048 (3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphomide) an inhibitor of kynurenine-3-monooxygenase (KMO) in shifting the balance towards the production of neuroprotective, kynurenic acid. Western blots were generated to indicate the expression of a range of proteins relevant to different aspects of CNS development including neuritogenesis, axon guidance, maintenance of synaptic plasticity, intracellular signalling and cell proliferation and migration. Within 5 h of Ro61-8048, there was a significant decrease in NR2A expression and increased NR2B in the embryo brains, with subsequent changes in SHH and NFB at 24 h post treatment. The litters were left undisturbed until weaning on P21 and other groups were allowed to develop to P60, at which time they euthanized and the brains removed for analysis. At P21, western blot analysis revealed significantly increased protein expression of the NR2A and NR2B subunits and postsynaptic density protein (PSD95). Among several neurodevelopmental proteins, the expression of NFB and proliferating cell nuclear antigen (PCNA) was increased, while reduced level of SHH was detected. We demonstrate here persisting changes in NR2A expression, with reduced level in the hippocampus while a raised level was noted in the cortex suggesting prenatal modulation of kynurenine pathway causes long lasting modifications of NMDA receptor composition and function. It is important to note that kynurenine pathway inhibition can generate a consistent set of long term changes in the SHH in which the levels of this protein remained repressed in some regional areas of the brain including hippocampus, cerebellum and cortex. We show that there are some common pathways that are affected by kynurenine pathway inhibition, and this early modulation tends to disrupt critical molecular processes that are known to be actively occurring at each specific developmental time. Overall, given these selective and differing developmental profile, an early life modulation of the kynurenine pathway might be expected to cause a sufficient disturbance of biological processes that are actively occurring at the time of exposure and also able to leave a series of molecular changes that persist into adulthood. This disruption is likely to influence the resulting physiology of the adolescent and adult brain and subsequently can lead to impairments in social behaviour. It is hoped that this study provides a broad analysis of the long term molecular effects of developmental kynurenine metabolism, and that it allows for a viable opportunity of potential therapeutic targets for disease intervention.
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Nilsson, Linda K. "Glutamatergic mechanisms in schizophrenia: role of endogenous kynurenic acid /." Stockholm : Dept. of Physiology and Pharmacology, Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-538-0/.
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Schwieler, Lilly. "Endogenous kynurenic acid and schizophrenia : physiological and pharmacological aspects /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-704-9/.
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Alexander, Kathleen Shannon. "Elevated Kynurenic Acid as an Animal Model of Schizophrenia." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1304691359.
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Cobb, Christina. "A Link Between Gut Microbes & Depression: Microbial Activation of the Human Kynurenine Pathway." Scholarship @ Claremont, 2018. http://scholarship.claremont.edu/cmc_theses/1799.
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Our gut microbiota is involved in human development, nutrition, and the pathogenesis of gut disorders, but has more recently been implicated as a possible mechanism in the pathophysiology of several brain disorders, including disorders of mood and affect, such as depression. Researchers have referred to this dynamic, bidirectional signaling pathway between the gut and the brain as the “gut-brain axis.” However, most research on this axis has been limited to rodent studies, and there has been little insight into the mechanism behind it. I propose that the kynurenine pathway, where tryptophan is converted to kynurenine, is a compelling mechanism mediating the gut microbiota’s influence on depression. Kynurenine is a metabolite associated with depression, and this pathway has been shown to be manipulated through probiotic (Lactobacillus reuteri) consumption. I propose to study a probiotic intervention in humans, which would assess tryptophan metabolism along the kynurenine pathway by measuring metabolites downstream of this pathway. Urine, feces and blood samples would be collected from two groups, control and probiotic treatment, on day zero and day thirty. Colonic biopsies would be obtained on day thirty, and various analyses would be run to measure metabolite concentrations from the collected samples. The results from this study will help clarify a mechanistic connection between gut microbes and depression via the kynurenine pathway. Additionally, findings could indicate that a probiotic intervention has the ability to influence depressive behavior via a two-pronged approach originating from the kynurenine pathway.
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Maurus, Michael [Verfasser]. "Kynurenin als neuer Marker zur Beurteilung der Entzündungsreaktion bei verschiedenen herzchirurgischen Eingriffen / Michael Maurus." Ulm : Universität Ulm, 2018. http://d-nb.info/1162540044/34.
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Kariyawasam, Sandhya Himani. "An investigation into the biochemical changes in Tourette syndrome and associated conditions with a potential for pharmacological manipulation." Thesis, Aston University, 1999. http://publications.aston.ac.uk/10977/.
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Kynurenine (KYN) is the first stable metabolite of the kynurenine pathway, which accounts for over 95% of tryptophan metabolism. Two previous studies by this research group reported elevated plasma KYN in Tourette syndrome (TS) patients when compared with age and sex matched controls and another study showed that KYN potentiated 5-HT2A-mediated head-shakes (HS) in rodents. These movements have been suggested to model tics in TS. This raised the questions how KYN acts in eliciting this response and whether it is an action of its own or of a further metabolite along the kynurenine pathway. In the liver, where most of the kynurenine pathway metabolism takes place under physiological conditions, the first and the rate limiting enzyme is tryptophan-dioxygenase (TDO) which can be induced by cortisol. In extrahepatic tissues the same step of the pathway is catalyzed by indoleamine-dioxygenase (IDO), which is induced by cytokines, predominantly interferon-y (INF-y). Plasma neopterin, which shows parallel increase with KYN following immune stimulation, was also found elevated in one of these studies positively correlating with KYN. In the present work animal studies suggested that KYN potentiates and quinolinic acid (QUINA) dose dependently inhibits the 5-HT2A-mediated HS response in mice. The potentiating effect seen with KYN was suggested to be an effect of KYN itself. Radioligand binding and phosphoinositide (PI) hydrolysis studies were done to explore the mechanisms by which kynurenine pathway metabolites could alter a 5-HT2A-receptor mediated response. None of the kynurenine pathway metabolites tested showed direct binding to 5-HT2A-receptors. PI hydrolysis studies with KYN and QUINA showed that KYN did not have any effect while QUINA inhibited 5-HT2A-mediated PI hydrolysis. Plasma cortisol determination in TS patients with elevated plasma KYN did not show elevated plasma cortisol levels, suggesting that the increase of plasma KYN in these TS patients is unlikely to be due to an increased TDO activity induced by increased cortisol. Attention deficit hyperactivity disorder (ADHD) is commonly associated with TS. Salivary cortisol detected in a group of children primarily affected with ADHD showed significantly lower salivary cortisol levels when compared with age and sex matched controls. Plasma tryptophan, KYN, neopterin, INF-y and KYN/tryptophan ratio and night-time urinary 6-sulphatoxymelatonin (aMT6s) excretion measured in a group of TS patients did not show any difference in their levels when compared with age and sex matched controls, but TS patients failed to show the expected positive correlation seen between plasma INF-y, neopterin and KYN and the negative correlation seen between plasma KYN and night-time urinary aMT6s excretion seen in healthy controls. The relevance of the kynurenine pathway, melatonin secretion and cortisol to Tourette Syndrome and associated conditions and the mechanism by which KYN and QUINA alter the 5-HT2A-receptor mediated HS response are discussed.
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Hara, Toshiaki, Fumiyuki Yamakura, Osamu Takikawa, et al. "Diazotization of kynurenine by acidified nitrite secreted from indoleamine 2,3-dioxygenase-expressing myeloid dendritic cells." Elsevier, 2008. http://hdl.handle.net/2237/11379.
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Phenis, David Anthony. "Performance of Adult Rats Exposed to Elevated Levels of Kynurenic Acid during Gestation in a Rodent Target Detection Task: A Translational Model for Studying the Effects of Cognitive Training." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu154211727456543.
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Linderholm, Klas. "Kynurenic acid in psychiatric disorders studies on the mechanisms of action /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-818-1/.
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Akhouayri, Idir Georges. "Gene silencing of the kynurenine pathway and melanotic lesions in the malaria mosquito vector anopheles gambiae." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445336.
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Sakurai, Masashi. "Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder." Kyoto University, 2020. http://hdl.handle.net/2433/259732.
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Hernandez-Martinez, Juan-Manuel. "Role of kynurenines and oxidative stress in the differentiation of SH-SY5Y cells." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6133/.
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Neuroblastoma is the most common solid extracranial tumour in children. The neuroblastoma SH-SY5Y cell line is a third successive subclone established from a metastatic bone tumour biopsy. It can be induced to differentiate (regress) into a neuronal phenotype when treated with any of several molecules including retinoic acid (RA). This characteristic has been exploited in several studies that use the SH-SY5Y cell line as a neuronal model. These studies have had far- reaching implications in shaping our understanding of certain key aspects of neurotoxicity and neurodevelopment yet their genuine relevance becomes evident when approached from an oncological point of view, as they provide information about the process underlying tumour regression which in turn can lead to the development of better therapies for the clinical management of this malignancy. It has been shown both in vitro and in vivo that several tumours constitutively catabolize the essential amino acid tryptophan (Trp) promoting cancer- associated inflammation, immune response suppression, immune escape and tumour outgrowth. The main degradation pathway of Trp is the kynurenine pathway: it involves its transformation into several bioactive compounds such as kynurenic acid (KA) and quinolinic acid (QA). QA has been implicated in several neurodegenerative diseases where it is believed to induce excitotoxic neuronal death through the activation of the N-methyl-D-aspartate (NMDA) receptor, a type of ionotropic glutamate receptor, as well as by causing oxidative stress and energy metabolism disruption. Conversely, KA acts as an NMDA receptor antagonist and exerts neuroprotection. Similarly, glutamate signaling and its dysregulation has been implicated in the development and progression of cancer. Furthermore, several glutamate receptor antagonists, including kynurenic acid, have been shown to inhibit the proliferation and migration of neoplastic cells. Conversely, it has recently been reported that QA increases the proliferation of SK-N-SH cells and protects gliomas against oxidative stress by acting as a precursor of NAD+. In view of all that has been mentioned thus far, the SH-SY5Y cell line was used as a model to investigate the effect of certain Trp metabolites such as QA, KAand 3-hydroxyanthranilic acid (3-HAA) on cellular morphology, viability and neurite extension. An important part of this study was to determine whether the available methods could reliably be employed to investigate these parameters in the SH-SY5Y cell line. It was confirmed that the acquired SH-SY5Y cell line retains its ability to differentiate and to die, and that both processes can be accurately quantified. Additionally, the optimal culturing conditions for the SH- SY5Y cell line were determined. Treatment with RA (10 μM) was used as a positive control of differentiated SH- SY5Y cells. Overall, the morphology adopted by cells after QA (50 μM) treatment was similar to the one that follows RA-induced differentiation. It was demonstrated that QA caused an increase in the neurite/soma ratio in SH-SY5Y cells, which was confirmed by Western blot analysis as evidenced by an increase in the total cellular content of β3-tubulin. These results were also confirmed by a neurite outgrowth assay that selectively quantified the neuritic mass present in cultures. However, unlike RA, QA did not decrease the levels of the neuronal proliferation marker doublecortin; the term neuritogenesis is therefore more appropriately used to refer to the series of morphological and molecular changes induced by QA in SH-SY5Y cells. The morphological changes induced by QA were not reproduced by application of NMDA, nor were they inhibited by blockade of the NMDA receptor with MK-801. Furthermore, SH-SY5Y cells were not susceptible to NMDA excitotoxic death. In view of this, the expression of GluN1 protein was determined by Western blot. GluN1 could not be detected in either undifferentiated or differentiated SH-SY5Y cells, confirming that QA-induced neuritogenesis occurs through a mechanism independent of NMDAR activation. The results herein contained suggest that the SH-SY5Y cell line does not have functional NMDARs, nonetheless it is recognized that a more exhaustive study would be necessary to fully establish which glutamate receptor subtypes are found in the SH-SY5Y cell line. The effect of QA on the production of reactive oxygen species (ROS) was also investigated. QA caused an increase in the intracellular levels of ROS as evidenced by an increase in the fluorescence of oxidised ethidium. Additionally QA-treatment caused an increase in the expression of NRF2, a transcriptionfactor that responds to oxidative stress and which has been implicated in ROS- induced differentiation in SH-SY5Y cells. In contrast, superoxide dismutase (SOD; 300 U/ml) significantly reduced the levels of ROS induced by QA treatment, which in turn caused an increase in cell proliferation and a reduction in the number of neurites. Similarly, diphenylene iodonium (DPI; an inhibitor of NADPH oxidase) also inhibited QA-induced neuritogenesis. These results suggest that the action mechanism of QA is mainly via the production of ROS, most likely superoxide (O2•-) through NADPH-oxidase. Interestingly, nicotinamide (1 nM-1mM; another precursor of NAD+) caused a dose dependent increase in the number of neurites and in the expression of β3- tubulin, which suggests that the action mechanism of QA may be mediated by metabolites of the nicotinate and Nam pathway, including NAD+ either before or after the induction of ROS. Cells were treated with 3-hydroxyanthranilic acid (3-HAA) in order to ascertain whether other pro-oxidant molecules could induce neuritogenesis as well. Single and repeated application of 3-HAA (100 μM) induced cell death in SH-SY5Y cells. Furthermore, when 3-HAA was delivered in combination with SOD, there was a shift in the IC50 values indicating that toxicity was potentiated by SOD. Catalase (CAT; 100 U/ml) afforded complete protection from the exacerbated damage induced by the single co-application of 3-HAA + SOD. However, when repeated treatments were performed, CAT no longer afforded any protection. Interestingly, the serum concentration in the medium did not affect the IC50 of 3-HAA but it did modulate the response to CAT, indicating that the specific ROS produced after 3-HAA treatment depend on the medium in which 3-HAA is delivered. At sublethal doses, 3-HAA interfered with the expression of NeuN (neuronal marker) through a mechanism that involves high production of ROS. The ability of some kynurenines to induce differentiation and cell death in SH- SY5Y cells may open new and exciting avenues of research. If these results can be confirmed in vivo they could impact the way in which certain neuroblastomas are treated.
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Laugeray, Anthony. "Etude du rôle de la voie de la kynurénine dans un modèle animale de dépression : le stress chronique imprédictible : approches biochimique et comportementale." Thesis, Tours, 2010. http://www.theses.fr/2010TOUR4013/document.
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Dans ce travail de thèse, nous nous sommes intéressés à mieux comprendre le rôle du métabolisme du tryptophane (TRP), et en particulier de la voie de la kynurénine (KYN), dans la physiopathologie des troubles dépressifs en utilisant un modèle murin de dépression - le stress chronique imprédictible modéré (Unpredictable Chronic Mild Stress = UCMS). Nous avons montré que 1) l'UCMS affecte de façon différentielle le métabolisme de la KYN selon qu'il se déroule en périphérie ou dans le SNC 2) l'UCMS induit l'accumulation de certains métabolites toxiques de la KYN en périphérie alors que dans le cerveau, l'effet est structure-dépendant 3) la concentration en KYN est inversement proportionnelle à la concentration en 5-HT dans le SNC 4) que l'activation de la voie KYN périphérique est positivement corrélée à l'expression de comportements anxio-dépressifs 5) que l'inhibition pharmacologique de la voie KYN a des effets antidépresseurs<br>During this thesis, we were interested in better understand the role of the kynurenine pathway (KP) in the pathophysiology of depressive disorders by using a murine model of depression - the Unpredictable Chronic Mils StressProcedure = UCMS). We have shown that 1) UCMS has different effects on peripheral and cerebral tissues 2) UCMS induces accumulation of some toxic KP metabolites in the periphery and the CNS 3) the cerebral level of KYN innegatively correlated to the level of 5-HT 4) activation of the peripheral KP is positively correlated to the expression of anxiety-like and depressive-like behaviors, only in UCMS mice 5) pharmacological inhibition of the KP have antidepressant properties
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Trecartin, Katelyn V. "Kynurenic acid and epigenetics: proposing a unified view of schizophrenia onset and pathology." Thesis, Boston University, 2013. https://hdl.handle.net/2144/21264.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.<br>Schizophrenia is a debilitation mental illness characterized by positive symptoms (mania and hallucinations), negative symptoms (flat affect), and cognitive impairments (learning and memory deficits). These symptoms arise from dysfunction of several neurotransmitter systems including the dopaminergic, seratonergic, cholinergic, and glutamatergic pathways. As such, treatment of this disease has been difficult due to the number of systems involved. Various theories dealing with maternal infection, chemical imbalance, genetics, and epigenetics have emerged postulating the origin of the disease. To date, there is no one unifying hypothesis that encompasses all of the behavioral and biological deficits manifested in schizophrenia. A review of the current research suggests a central role of kynurenic acid (KYNA) in all of these theories. As an endogenous antagonist of cholinergic and glutamatergic receptors, KYNA has been shown to mimic the disease when administered exogenously. Additionally, KYNA levels appear to be elevated in the brains of schizophrenics. Understanding how this chemical works and how it becomes elevated in the first place will be key to understanding the pathology of schizophrenia and developing effective treatments.<br>2031-01-01
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Wilson, Kris. "Novel screening techniques for the discovery of human KMO inhibitors." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/18743.
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Kynurenine 3-monooxygenase (KMO) is an enzyme central to the kynurenine pathway of tryptophan degradation. KMO is emerging as an increasingly important target for drug development. The enzyme is implicated in the development and progression of several neurodegenerative disorders, in the regulation of the immune response and in sterile systemic inflammation. Production of recombinant human enzyme is challenging due to the presence of transmembrane domains, which localise KMO to the outer mitochondrial membrane and render KMO insoluble in many in vitro expression systems. Although several in vitro KMO assay techniques have been reported in the literature these methods are typically insensitive or require purified protein for use in high-throughput screening assays of human KMO enzyme. The first report of bacterial expression of soluble active human KMO enzyme is described here. Fusion protein tags were used to optimise soluble expression and enable characterisation and partial purification of the active protein constructs. Functional enzyme was used to develop several novel high-throughput drug screening techniques for the discovery of inhibitors specifically targeting human KMO. These screening techniques were fully characterised and validated using known KMO inhibitors from the patent literature. One of the novel KMO assay techniques was implemented for compound screening and several hit compounds were identified, validated and their in vitro DMPK characteristics determined. In addition to assay development, KMO was characterised at the cellular level when overexpressed in HEK293 cells. These experiments indicated that KMO overexpressing cells undergo bidirectional adaptation via alteration of kynurenine pathway homeostasis. As a result, these cells are protected from cytotoxicity mediated by 3-hydroxykynurenine (3-HK), the toxic product of KMO catalysis. The development of novel high throughput screening techniques targeting KMO has enabled screening of potential new inhibitors specifically targeting the human enzyme. Implementation of these screening assays will allow accelerated and improved discovery and development of novel KMO inhibitors for the potential treatment of numerous disease states.
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Yan, Edwin B., Tony Frugier, Chai K. Lim, et al. "Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans." BioMed Central, 2015. http://hdl.handle.net/10150/610324.
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ABSTRACT: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.
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Zmarowski, Amy L. "Astrocytes Regulate Cortical Ach Release Via Kynurenic Acid: Implications For Cognitive Impairments In Schizophrenia." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1217199677.
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Bellac, Caroline. "Pathomechanisms of bacterial meningitis based on transcriptome analysis : role of kynurenine 3-hydroxylase and galectin-3/-9 in brain injury /." [S.l.] : [s.n.], 2007. http://www.zb.unibe.ch/download/eldiss/07bellac_c.pdf.
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Erhardt, Sophie. "Importance of endogenous kynurenic acid in brain catecholaminergic processes and in the pathophysiology of schizophrenia /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4889-5/.
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Hara, Toshiaki, Nanako Ogasawara, Hidetoshi Akimoto, et al. "High-affinity uptake of kynurenine and nitric oxide-mediated inhibition of indoleamine 2,3-dioxygenase in bone marrow-derived myeloid dendritic cells." Elsevier, 2008. http://hdl.handle.net/2237/11381.
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Tan, Vanessa. "Identification of biomarkers for MND, and understanding the potential role of the cyanotoxin BMAA in neurodegeneration Involvement of Quinolinic Acid in the Neuropathogenesis of amyotrophic lateral sclerosis Detection of the Cyanotoxins L-BMAA Uptake and Accumulation in Primary Neurons and Astrocytes." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS590.
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La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative dévastatrice dont les causes sont inconnues et pour laquelle il n’existe aucun traitement ni marqueur spécifique. Dans ce contexte, nous avons étudié le rôle de la voie métabolique des kynurénines impliquée dans la production de métabolites neuroactifs qui peuvent être immunomodulateurs, neuroprotecteurs ou à l’inverse neurotoxiques. Dans une étude longitudinale du sérum de 66 patients atteints de SLA, nous avons évalué le profil de 10 métabolites de la voie des kynurénines par chromatographie HPLC et spectrographie GC/MS. Nous avons mis en évidence un profil métabolique, spécifique de la progression de la SLA, qui pourrait être utilisé comme biomarqueur pour suivre l’évolution de la maladie. En collaboration avec la clinique de la SLA de l’Université Macquarie de Sydney, nous avons constitué une banque d’échantillons de patients atteints de SLA et d’autres maladies neurodégénératives (Parkinson, Alzheimer) ce qui permettra de rechercher à plus grande échelle les facteurs responsables de l’étiologie et du décours de la SLA. Dans une seconde partie, nous avons évalué le potentiel neurotoxique de la (BMAA), une cyanotoxine dont la présence dans l’environnement est corrélée avec une incidence accrue de la SLA. A l’aide de modèles cellulaires permettant de modéliser des voies neuro-anatomiques in vitro. Nous avons démontré que la BMAA provoque une déstructuration des réseaux de neurones et mis en évidence la capacité de cette biotoxine, qui s’apparente à un acide aminé, de se propager de cellule à cellule et donc potentiellement de se disperser dans le système nerveux central<br>Motor Neuron Disease (MND) or Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disease with no biological diagnostic markers, no effective treatment, and no cure. We investigate the immune related Kynurenine Pathway (KP) for a role in ALS. The production of neuroactive metabolites during the KP indicate that there is an overlap with the mechanisms of ALS, particularly with the neurotoxin quinolinic acid. Subsequently, we investigate the KP metabolome, analysing 10 metabolites using biochemical analyses including High Performance Liquid Chromatography and Gas Chromatography/Mass Spectrometry. Using serum from a longitudinal cohort of 66 ALS patients, we establish a potential for KP metabolomics to be used a biomarker for ALS. To increase specificity and reliability of these results, in collaboration with Macquarie University Neurology, we established a Neurodegenerative Diseases Biobank to collect patient biological samples. These samples would facilitate future investigations into the mechanisms, genetics, biomarkers, and to detect the presence of toxic compounds such as metals, or β-methylamino-L-alanine (BMAA). We describe the establishment of the biobank as a case study for future references. BMAA is known to be neurotoxic, and we investigate its role ALS. We reveal its role in promoting axonal degeneration and neuronal death, and show for the first time, its ability to spread transcellularly
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Favennec, Marie. "Etude de la voie des kynurénines dans l'obésité humaine." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S037/document.
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Le tryptophane, un acide aminé essentiel, est soit utilisé pour la synthèse protéique et la synthèse de sérotonine, soit dégradé en plusieurs métabolites appelés collectivement les kynurénines. L’expression et l’activité des enzymes de la voie des kynurénines sont stimulées par l’inflammation. La synthèse des kynurénines est donc susceptible d’être augmentée chez les individus obèses. En effet, l’obésité est caractérisée par une inflammation chronique à bas bruit du tissu adipeux, reflétée par l’augmentation de facteurs inflammatoires circulants qui contribuent à l’apparition de l’insulinorésistance et du diabète de type 2. Plusieurs métabolites de la voie des kynurénines pourraient être des facteurs de risque pour le développement de l’insulinorésistance. La chirurgie bariatrique est actuellement le traitement le plus efficace pour l’obésité sévère, elle permet une perte de poids significative ainsi qu’une diminution des facteurs inflammatoires circulantes et une amélioration de l’insulinorésistance et du diabète. Il a été démontré que l’expression d’IDO1, la première enzyme de la voie des kynurénines, est plus élevée dans le tissu adipeux des individus obèses. Le ratio kynurénine sur tryptophane, qui reflète l’activité D’IDO1, est également augmenté chez les individus obèses.Notre objectif a été de caractériser l’expression des enzymes de la voie des kynurénines dans le tissu adipeux et d’évaluer les concentrations des kynurénines dans les sérums de patientes obèses pour rechercher si certains de ces facteurs pouvaient être reliés à l’apparition du diabète. Ces études ont été réalisées dans une cohorte de femmes obèses normoglycémiques et diabétiques. Puis dans un second temps nous avons étudié les conséquences de la perte de poids induite par la chirurgie bariatrique sur les concentrations circulantes des kynurénines et évalué si les variations des concentrations des kynurénines pourraient expliquer en partie l’amélioration du diabète observée après la chirurgie.Dans cette étude, nous avons montré que plusieurs enzymes de la voie sont plus exprimées dans le tissu adipeux des individus obèses que des minces. L’augmentation de l’expression des enzymes dans le tissu adipeux des individus obèses provient d’une part de la présence de macrophages pro-inflammatoires dans le tissu adipeux et également de la réponse des adipocytes aux stimuli pro-inflammatoires. En parallèle, nous avons montré que les concentrations circulantes des kynurénines et le ratio kynurénine sur tryptophane augmentent avec l’IMC et qu’ils diminuent un an après la chirurgie bariatrique. Dans notre étude, comme attendu, la chirurgie bariatrique est associée à une amélioration voire à une rémission du diabète. Nous avons montré également que le maintien des concentrations d’acide kynurénique et d’acide quinolinique sont associés respectivement à la rémission du diabète et à l’amélioration des traits cliniques qui définissent le diabète. La diminution des concentrations en acide xanthurénique après la chirurgie est associée au contraire à une amélioration des traits cliniques qui définissent le diabète<br>Tryptophan, an essential amino acid, is either used in protein synthesis or metabolized via the serotonin or the kynurenine pathway. The kynurenine pathway is the main route of tryptophan degradation and generates several metabolites collectively called “kynurenines”. The expression of kynurenine pathway enzymes is induced by inflammatory mediators. Consequently kynurenine synthesis could be induced in individuals with obesity. In fact, obesity is characterized by a chronic low grade inflammation of the adipose tissue reflected by increased serum levels of inflammatory factors which are known to contribute to the development of obesity-induced insulino-resistance. Some metabolites of the kynurenine pathway have been proposed to be risk factors for the development of insulin resistance. Bariatric surgery is currently the most effective treatment for severe obesity and results in a significant weight loss, a decreased level of inflammatory factors and an amelioration of glucose homeostasis. The first enzyme of the kynurenine pathway, IDO1, is known to be more expressed in the adipose tissue of individuals with obesity compared to lean individuals. The kynurenine over tryptophan ratio reflects the activity of IDO1 and is also increased in individuals with obesity.Our objective was to characterize the expression of the kynurenine pathway enzymes in the adipose tissue of women with severe obesity and to evaluate serum levels of the kynurenine pathway metabolites to determine whether these factors could be associated with the appearance of diabetes. This study was performed in women with severe obesity with or without type 2 diabetes. Then we investigated the consequences of weight loss induced by bariatric surgery on levels of circulating kynurenines in order to evaluate whether these variations could explain the improvement in glucose control and type 2 diabetes remission after one year follow-up.In this study, we have shown that several kynurenine pathway enzymes were more expressed in the adipose tissue of women with obesity compared to lean controls. This increase is due to the presence of pro-inflammatory macrophages in the adipose tissue and also comes from the adipocyte response to inflammatory stimuli. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. As expected, bariatric surgery is associated with the improvement and even the remission of type 2 diabetes. We have shown that higher levels of kynurenic acid and quinolinic acid one year after the surgery are associated respectively with type 2 diabetes remission and better glucose homeostasis and that lower levels of xanthurenic acid are associated with better glucose homeostasis
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Okada, Sabrina Sayori. "Regulação cruzada entre peroxidases e indolamina 2,3 dioxigenase no controle da metabolização do triptofano." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-21012011-151605/.
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Triptofano (TRP) é metabolizado por duas vias, a via serotonérgica e a via das quinureninas. Na via serotonérgica, TRP é metabolizado a serotonina (5-HT) e, em algumas células, à melatonina (MLT) que pode ser oxidada à N1-acetil-N2-formil-5- metoxiquinuramina (AFMK) e N1-acetil-5-metoxiquinuramina (AMK) por ação de peroxidases. Na via das quinureninas o TRP é diretamente metabolizado à N formilquinurenina (NFK) e em seguida a quinurenina (QUIN). A enzima indolamina 2, 3 dioxigenase (IDO) é uma das responsáveis por esta reação. Dada a importância da IDO na tolerância imunológica e pelo fato desta enzima ser induzível nos propusemos a avaliar a existência de uma regulação cruzada entre esta enzima e a via serotonérgica. Avaliando a interferência de AMK sobre a ação de IDO e a interferência de QUIN sobre a formação de AFMK por peroxidases, observamos uma possível interação entre as vias. AMK é um inibidor competitivo clássico de IDO e o Ki encontrado foi de 0,98 mM. QUIN é um inibidor acompetitivo linear simples da formação de AFMK e o Ki encontrado foi de 0,1 mM. A inibição da formação de AFMK também ocorre para a peroxidase humana (mieloperoxidase, MPO). Além de representarem uma regulação cruzada utilizada in vivo, as inibições encontradas podem ser relevantes para a proposta de novos inibidores de IDO e MPO na terapia imunomodulatória. Dado o nosso interesse pelas enzimas IDO e MPO, avaliamos ainda a localização intracelular destas enzimas em células de peritônio de camundongo, tanto residente como ativada com concanavalina A (Con A). O estímulo com Con A representa uma ativação de linfócitos T mediado por interferon gama (IFN-γ) e foi usado como modelo experimental para avaliar condições de localização em células ativadas. Por imunocitoquímica verificamos que IDO e MPO localizam-se próxima à membrana plasmática sendo que uma leve dispersão apenas de MPO foi observada em células ativadas com Con A. A localização intracelular das duas enzimas é no citoplasma, vesículas e núcleo. Curiosamente, verificamos MPO em células isoladas e também em agrupamentos celulares de duas ou mais células. Por citometria de fluxo identificamos macrófagos, linfócitos B1 e agrupamentos celulares como células que contém MPO. A mobilização de MPO durante a ativação celular, a presença de MPO em linfócitos e a presença de MPO e IDO em núcleos são informações novas que sugerem novas atividades para estas enzimas.<br>Tryptophan (TRP) is metabolized by two mains pathways, the serotoninergic pathway and the kynurenine pathway. In the serotoninergic pathway, TRP is metabolized to serotonin (5-HT) and, in some cells, to melatonin (MLT). The later can even be oxidized to acetyl-N1-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5 -methoxykynuramine (AMK) by peroxidases. In the kynurenine pathway, TRP is metabolized to N-formylkynurenine (NFK) and to kynurenine (KYN). Indoleamine 2, 3 dioxygenase (IDO) is one of those responsible for this reaction. Since IDO is importat in immune tolerance and the fact that this enzyme is inducible by cytokines we proposed whether there is a cross regulation between this enzyme and the serotoninergic pathway. A possible interaction between MLT and TRP oxidation pathways was shown by the AMK influence on IDO activity and QUIN interference on AFMK formation by peroxidases. AMK was shown to be an IDO classical competitive inhibitor with a Ki of 0.98 mM. QUIN was a peroxidase (horseradish peroxidase, HRP) classical uncompetitive inhibitor and Ki was found to be 0,1 mM. AFMK formation inhibition was also found in human peroxidase (myeloperoxidase, MPO). Beyond the in vivo crosstalk, new IDO and MPO inhibitors in immunomodulatory therapy would be proposed by the compounds shown in this study. Given our interest in IDO and MPO, we also evaluated their intracellular localization in both resident and concanavalin A (Con A) activated mice peritoneum cells. Con A stimulation is a IFN-γ mediated T lymphocytes activation and was our experimental model to evaluate activated cells. In light microscopy we observed IDO and MPO localization near the membrane and MPO only had a dispersed localization in Con A activated cells. Cytoplasm, nucleus and vesicles were the intracellular localization of both enzymes. Interestingly, we found MPO in isolated cells and in cell clusters of two or more cells. MPO was founded on macrophages, B1 cells and cell clusters by flow cytometry. The MPO mobilization during cell activation, the presence of MPO in lymphocytes and the presence of MPO and IDO in nuclei are new informations to suggest new activities for these enzymes.
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Hang, Regina [Verfasser]. "ATP, HMGB1, and S100A4 promote immunosuppressive mesenchymal stromal cells by enhancing their kynurenine production : impact of necrosis on tumor-associated MSCs / Regina Hang." Ulm : Universität Ulm, 2019. http://d-nb.info/1186139927/34.
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Campbell, Andrew B. "Regulation of prefrontal glutamate by the endogenous neuromodulator kynurenic acid as measured by rapid electrochemistry relevance to schizophrenia /." Connect to resource, 2010. http://hdl.handle.net/1811/45374.
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Pershing, Michelle L. "Interactions Between Prenatal Kynurenic Acid Exposure and Adolescent Brain Development in the Emergence of Cognitive Deficits in Schizophrenia." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417275379.
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Marchi, Alexandre Froes. "Produção de quinurenina em modelos experimentais de restrição de sono e obesidade." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-03062015-165904/.
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A via das Quinureninas (Via Quin) representa a principal via catabólica do metabolismo do triptofano (Trp) e é essencial para diversos processos fisiológicos. No fígado, o Trp é catalisado por triptofano 2,3-dioxigenase (TDO) quinurenina (Quin). A mesma reação também pode ser catalisada pela enzima indolamina 2,3-dioxigenase (IDO), produzida por células imunológicas. Em alguns processos patológicos, há um aumento do consumo de Trp pela Via Quin, que gera compostos que estão relacionados ao processo de imunotolerância. No presente estudo, foram selecionados dois modelos que mimetizam situações associadas às alterações da resposta imunológica: a restrição de sono e a obesidade. A partir do conhecimento das alterações na resposta imune nessas condições, geramos a hipótese de que parte do mecanismo se dê a partir da indução do catabolismo de Trp pela via Quin. Desse modo, foram investigadas as concentrações séricas e hepáticas de Trp nesses modelos experimentais, modelos esses que foram utilizados em outros projetos do nosso grupo de pesquisa. Não houve diferença significativa na concentração de Quin sérica e hepática entre os camundongos C57BL/6J restritos de sono (3 hs/15 dias), privação de sono paradoxal (72 hs) e período rebote (24 hs). A razão Quin/Trp também não diferiu entre os grupos RS e controle. Igualmente não houve diferenças estatísticas na concentração de Quin plasmática nos modelos privação de sono paradoxal e período rebote realizados em ratos Wistar. O mesmo foi observado em camundongos Swiss e camundongos C57BL/6J submetidos a protocolos experimentais de obesidade: ração hiperlipídica (21 dias) e de síndrome metabólica (20 semanas de ração hiperlipídica). Tais resultados sugerem que as alterações na resposta imunológica nesses quadros não estão associadas ao catabolismo de Trp.<br>The Kynurenine pathway (Kyn pathway) is the major catabolic pathway of tryptophan metabolism (Trp) and it is essential for many physiological processes. In the liver, Trp is catalyzed by tryptophan 2,3-dioxygenase (TDO), producing kynurenine (Kyn). The same reaction can also be catalyzed by the enzyme indoleamine 2,3-dioxygenase (IDO), produced by immune cells. In some pathological conditions, there is a high Trp consumption by Kyn pathway, that generate compounds related to immune tolerance. In this study, we chose two models strongly associated with changes in the immune response: sleep restriction and obesity. From the knowledge that there are immune response alterations in those conditions, we generated the hypotesis that in part, those alterations are correlated with induction the Trp catabolism by Kyn pathway. Thus, serum and liver concentrations of Trp and Kyn were investigated in these experimental models that have been used in other projects of our research group. There was no significant difference in concentration of Kyn in serum and liver among mice C57BL/6J induced to restricted sleep (3 hours / 15 days), paradoxical sleep deprivation (72 hours) and rebound period (24 hours). The Kyn/Trp ratio did not differ between control group and RS group. Also there were no statistical differences in plasma concentration of Kyn in paradoxical sleep deprivation and rebound period models performed in rats Wistar. The same profile was also observed in Swiss e C57BL/6J mice subjected to experimental obesity protocols: fat diet (21 days) and metabolic syndrome (20 weeks of fat diet). These results suggest that changes in the immune response in the conditions tested above are not associated with Trp catabolism.
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Reis, Dênis Augusto Santana. "Ativação supraespinal da via das quinureninas contribui para a manutenção da dor neuropática." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-29052015-154850/.
Full textAbstract:
Introdução: Um fator que pode contribuir para o desenvolvimento da dor neuropática é a modulação negativa da via descendente da dor pelo aumento da degradação do triptofano pela ativação da enzima indoleamina 2,3-dioxigenase 1 (IDO1) ou a ativação da via descendente facilitatória da dor por um agonista glutamatérgicos produzido pela enzima quinurenina 3 monoxigenase (KMO). Objetivo: Foi avaliar a participação das enzimas IDO1 e a KMO presente na substância cinzenta periaquedutal (PAG) e no bulbo rostral ventromedial (RVM) no desenvolvimento da dor neuropática em camundongos induzida pelo modelo SNI. Metodologia: A indução da neuropatia experimental foi realizada de acordo com (Bourquin et al., 2006). A expressão da IDO1 e KMO foi realizada pela técnica de Western blotting. A administração de drogas foi realizada por via oral, intraperitoneal, intratecal e intracerebroventricular (i.c.v.). Resultados: Foi observado o aumento da expressão da enzima IDO1 no RVM (7 dias) e PAG (3, 7, 14 e 21 dias) após SNI. A microinjeção de Norharmane no espaço i.c.v. reduziu a hipersensibilidade mecânica no 7, 14 e 21 dias após SNI. Corroborando com esses achados, animais deficientes para a enzima IDO1 submetidos a SNI não desenvolvem a hipersensibilidade mecânica. Além disso, a expressão da enzima KMO aumenta significativamente no 7 e 14 dias no RVM e 7 dias na PAG após SNI. Por conseguinte, a administração oral de JM6, pró-droga de liberação lenta do Ro61-8048, ou Ro61-8048 (inibidor da KMO) no espaço i.c.v. reduziu significativamente a hipersensibilidade mecânica nos dias 7, 14 ou 21 após SNI. Sabendo que a expressão da enzima IDO1 é modulada pela citocina IFN-, verificamos que os animais deficientes para a citocina IFN- apresentam hipersensibilidade mecânica reduzida. Ainda, os animais IFN- KO possuem expressão reduzida da IDO1 no RVM 7 dias e na PAG 14 dias após a SNI. Em adição, a microinjeção de doses crescentes de IFN- no espaço i.c.v. induz uma hipernocicepção mecânica em camundongos naives. Constatamos também que animais CD4+ KO, mas não os animais CD8+ KO apresentam reduzida expressão da enzima IDO1 no RVM e na PAG e consequentemente menor hipersensibilidade mecânica após SNI. A microinjeção dos metabolitos da via das quinureninas, no espaço i.c.v. de camundongos causou hipersensibilidade mecânica, sendo o QUIN o mais potente. Sugerimos que a ativação da via das quinureninas seja dependente da ativação do receptor NMDA, visto que o pré-tratamento local com o MK801 (antagonista seletivos dos receptores NMDA) reverte os efeitos nociceptivos induzidos pelos metabólitos. Além disso, o efeito nociceptivo induzido por QUIN depende ativação da via descendente facilitatória. Constatamos que os animais neuropáticos exibem um comportamento do tipo depressivo e esse comportamento não é observado em animais IFN- KO e CD4KO. Por último, avaliamos a participação da via das quinureninas no desenvolvimento do comportamento depressivo associado à SNI e constatamos que esse comportamento depende da ativação das enzimas IDO1 e KMO. Conclusão: Os resultados sugerem que as enzimas IDO1 e KMO, localizadas em regiões supraespinais desempenham um importante papel no desenvolvimento da dor neuropática, assim como da comorbidade depressão. Além disso, a expressão da IDO1 é dependente da sinalização via citocina IFN- e células CD4+. O mecanismo responsável pelo desenvolvimento da hipersensibilidade neuropática deve-se tanto a redução dos níveis de triptofano/5-HT, diminuição da eficiência da via descendente inibitória, quanto ao aumento dos níveis de QUIN, que ativa a via descendente facilitatória da dor.<br>Introduction: One factor that may contribute to the development of neuropathic pain is the negative modulation of the descending pain pathway by increased degradation of the activation of tryptophan by enzyme indoleamine 2,3-dioxygenase1 (IDO1) or activation of the descending facilitatory pain pathway for a glutamate agonist produced by the enzyme kynurenine 3 monooxygenase (KMO). Aim: We evaluate the role of IDO1 and KMO in the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM) in the development of neuropathic pain in mice induced by SNI model. Methods: Induction of experimental neuropathy was performed according to (Bourquin et al. 2006). The expression of IDO1 and KMO was carried out by Western blotting technique. The drug administration was performed orally, intraperitoneally and intracerebroventricularly (i.c.v) Results. We observed increased IDO1 expression in the RVM (7 days) and PAG (3, 7, 14 and 21 days) after SNI. The microinjection Norharmane in i.c.v. space reduced mechanical hypersensitivity in the 7, 14 and 21 days after SNI. Corroborating these findings, mice deficient for the enzyme IDO1 undergoing SNI did not develop mechanical hypersensitivity. Furthermore, the KMO expression was significantly increased in the 7 and 14 days in the RVM and 7 days in PAG after SNI. Therefore, oral administration of JM6, prodrug slow release from Ro61-8048 or Ro61-8048 (KMO inhibitors) within i.c.v. significantly reduced the mechanical hypersensitivity at day 7, 14 or 21 after SNI. Knowing that the expression of IDO1 enzyme is modulated by IFN- cytokine, it was found that animals deficient for IFN- cytokine have reduced mechanical hypersensitivity. Moreover, IFN- ko animals have reduced expression of IDO1 RVM 7 days and 14 days after SNI in the PAG. In addition, microinjection of increasing doses of IFN- in i.c.v. induced mechanical hyperalgesia. We also found that CD4 + KO animals, but not CD8 + KO animals showed reduced expression of the enzyme IDO1 RVM and PAG and consequently lower mechanical hypersensitivity after SNI. The microinjection of the main metabolites of kynurenine pathway into the i.c.v. spaces induced mechanical hypersensitivity, QUIN being the most potent. We suggest that the activation of the kynurenine pathway was dependent of NMDA receptor activation, whereas the spot pre-treatment with MK801 (selective NMDA receptor antagonist) reverses the effects induced by noxious metabolites. After that, the microinjection into i.c.v. spaces of MK801 reduced mechanical hypersensitivity after SNI. Furthermore, nociceptive effect induced by QUIN depends activation of the descending facilitatory. We found that the neuropathic animals exhibit depressive-like behavior and this behavior is not observed in IFN- KO and CD4KO mice. Finally, we evaluate the participation of kynurenine pathway in the development of depressive-like behavior associated with SNI and found that this behavior depends on the activation of IDO1 and KMO Conclusion: These results suggest that IDO1 and KMO enzyme, located in supraspinal regions play a role in the development of neuropathic pain as well as comorbidity depression. Furthermore, the expression of IDO1 are dependent on signaling via cytokine IFN- and CD4+ cells. The mechanism responsible for the development of neuropathic hypersensitivity is due to both reduced levels of tryptophan/5-HT decrease the descending inhibitory pain pathway efficiency, as the increased levels of QUIN, which activates the descending facilitatory pain pathway.