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Gilles J Guillemin - One of the best experts on this subject based on the ideXlab platform.
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Microbiota Alterations in Alzheimer's Disease: Involvement of the Kynurenine Pathway and Inflammation.
Neurotoxicity Research, 2019Co-Authors: Michelle L. Garcez, Kelly R. Jacobs, Gilles J GuilleminAbstract:Alzheimer's disease (AD) is a neurodegenerative disease considered the major cause of dementia in the elderly. The main pathophysiological features of the disease are neuronal loss (mainly cholinergic neurons), glutamatergic excitotoxicity, extracellular accumulation of amyloid beta, and intracellular neurofibrillary tangles. However, other pathophysiological features of the disease have emerged including neuroinflammation and dysregulation of the Kynurenine Pathway (KP). The intestinal microbiota is a large and diverse collection of microorganisms that play a crucial role in regulating host health. Recently, studies have highlighted that changes in intestinal microbiota contribute to brain dysfunction in various neurological diseases including AD. Studies suggest that microbiota compositions are altered in AD patients and animal models and that these changes may increase intestinal permeability and induce inflammation. Considering that microbiota can modulate the Kynurenine Pathway and in turn neuroinflammation, the gut microbiome may be a valuable target for the development of new disease-modifying therapies. The present review aims to link the interactions between AD, microbiota, and the KP.
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Central Kynurenine Pathway shift with age in women.
Journal of Neurochemistry, 2016Co-Authors: Josien De Bie, Gilles J Guillemin, Jade Guest, Ross GrantAbstract:Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The Kynurenine Pathway, a major metabolic Pathway of tryptophan is altered in the majority of neurodegenerative disorders. In this study, we have analysed CSF samples from 49 healthy women across a wide age range (0-90) for Kynurenine Pathway metabolites and the inflammatory marker neopterin. Our results show central tryptophan metabolism is increased with age in women, with an apparent shift towards the neurotoxin quinolinic acid. We also observed an increase in central levels of the inflammatory marker neopterin with age and a positive correlation between neopterin and Kynurenine Pathway activation. We conclude that, the changes that occur in the Kynurenine Pathway as a result of normal ageing are mechanistically linked to increased inflammatory signalling and have some explanatory potential with regard to age-associated degenerative diseases in the CNS. Management of health in ageing and (preventative) treatment would do well to look to the Kynurenine Pathway for potentially novel solutions. Both the inflammation marker neopterin and Kynurenine Pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), Kynurenine and quinaldic acid (QA) were increased, 3-hydroxyKynurenine (3HK) was decreased and 3-hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.
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Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.
PLOS ONE, 2015Co-Authors: Simon Jones, Gilles J Guillemin, Chai K. Lim, Josien De Bie, Nunzio F. Franco, Bianca Varney, Gayathri Sundaram, David A. Brown, Bruce J BrewAbstract:The Kynurenine Pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of Kynurenine Pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key Kynurenine Pathway enzymes and the main Kynurenine Pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), Kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of Kynurenine Pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the Kynurenine Pathway (Kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify Kynurenine Pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.
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The Kynurenine Pathway of tryptophan degradation is activated during osteoblastogenesis.
STEM CELLS, 2014Co-Authors: Christopher Vidal, Gilles J Guillemin, Chai K. Lim, Nicholas H. Hunt, Helen J. Ball, Brigitte Santner-nanan, Ralph Nanan, Gustavo DuqueAbstract:The mechanisms involved in the anabolic effect of interferon gamma (IFNγ) on bone have not been carefully examined. Using microarray expression analysis, we found that IFNγ upregulates a set of genes associated with a tryptophan degradation Pathway, known as the Kynurenine Pathway, in osteogenic differentiating human mesenchymal stem cells (hMSC). We, therefore, hypothesized that activation of the Kynurenine Pathway plays a role in osteoblastogenesis even in the absence of IFNγ. Initially, we observed a strong increase in tryptophan degradation during osteoblastogenesis with and without IFNγ in the media. We next blocked indoleamine 2,3-dioxygenase-1 (IDO1), the most important enzyme in the Kynurenine Pathway, using a siRNA and pharmacological approach and observed a strong inhibition of osteoblastogenesis with a concomitant decrease in osteogenic factors. We next examined the bone phenotype of Ido1 knockout (Ido1(-/-)) mice. Compared to their wild-type littermates, Ido1(-/-) mice exhibited osteopenia associated with low osteoblast and high osteoclast numbers. Finally, we tested whether the end products of the Kynurenine Pathway have an osteogenic effect on hMSC. We identified that picolinic acid had a strong and dose-dependent osteogenic effect in vitro. In summary, we demonstrate that the activation of the Kynurenine Pathway plays an important role during the commitment of hMSC into the osteoblast lineage in vitro, and that this process can be accelerated by exogenous addition of IFNγ. In addition, we found that mice lacking IDO1 activity are osteopenic. These data therefore support a new role for the Kynurenine Pathway and picolinic acid as essential regulators of osteoblastogenesis and as potential new targets of bone-forming cells in vivo.
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The Kynurenine Pathway
Amyotrophic Lateral Sclerosis, 2012Co-Authors: Yiquan Chen, Gilles J GuilleminAbstract:The Kynurenine Pathway represents a major route for the catabolism of tryptophan (TRP). In the body, TRP is transported around the periphery either bound to albumin (90%) or in free form (10%), the two states existing in equilibrium (McMenamy 1965). However, only free form TRP can be transported across the blood-brain barrier (BBB) by the competitive and nonspecific L-type amino acid transporter (Hargreaves and Pardridge 1988). Once in the central nervous system (CNS), TRP acts as a precursor to several metabolic Pathways, such as for the synthesis of Kynurenine (KYN), serotonin, melatonin and protein (Fig. 1) (Ruddick et al. 2006).
Lena Brundin - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine Pathway metabolites and suicidality.
Neuropharmacology, 2017Co-Authors: Elena Y. Bryleva, Lena BrundinAbstract:Suicide is a major global problem, claiming more than 800,000 lives annually. The neurobiological changes that underlie suicidal ideation and behavior are not fully understood. Suicidal patients have been shown to display elevated levels of inflammation both in the central nervous system and the peripheral blood. A growing body of evidence suggests that inflammation is associated with a dysregulation of the Kynurenine Pathway in suicidal patients, resulting in an imbalance of neuroactive metabolites. Specifically, an increase in the levels of the NMDA receptor agonist quinolinic acid and a simultaneous decrease in neuroprotective metabolites have been observed in suicidal patients, and may contribute to the development of suicidality via changes in glutamate neurotransmission and neuroinflammation. The cause of the dysregulation of Kynurenine metabolites in suicidality is not known, but is likely due to differential activity of the involved enzymes in patients. As knowledge in these areas is rapidly growing, targeting the Kynurenine Pathway enzymes may provide novel therapeutic approaches for managing suicidal behavior. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
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Suicidality and Activation of the Kynurenine Pathway of Tryptophan Metabolism
Inflammation-Associated Depression: Evidence Mechanisms and Implications, 2016Co-Authors: Elena Y. Bryleva, Lena BrundinAbstract:A recent report by the World Health Organization declared suicide to be a major global problem. With more than 800,000 lives lost each year, suicide is calculated to be the 14th leading cause of death around the world. While the biological mechanisms causing suicidal ideation and behavior are not fully understood, increased levels of inflammation, arising from various sources, have been detected in the central nervous system and the peripheral blood of suicidal patients and suicide completers. Inflammation induces the Kynurenine Pathway of tryptophan metabolism, which generates a range of metabolites with potent effects on neurotransmitter systems as well as on inflammation. Recent evidence indicates that a dysregulation of the enzymes in the Kynurenine Pathway may be present in suicidal patients, with a resulting imbalance of metabolites that modulate glutamate neurotransmission and neuroinflammation. As the body of research in these areas grows, targeting the Kynurenine Pathway enzymes and metabolites may provide novel therapeutic opportunities for detection, treatment, and ultimately prevention of suicidal behavior.
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Ongoing episode of major depressive disorder is not associated with elevated plasma levels of Kynurenine Pathway markers
Psychoneuroendocrinology, 2015Co-Authors: Johan Dahl, Lena Brundin, Ole A. Andreassen, Robert Verkerk, Ulrik Fredrik Malt, Leiv Sandvik, Heidi OrmstadAbstract:Summary Background It has been suggested that the development of depressive symptoms as a result of cytokine therapy is attributable to cytokine-induced elevated activity of the Kynurenine Pathway. The few studies of this mechanism in patients with common major depressive disorder (MDD) have yielded inconsistent results. The aim of the present study was to identify markers of the Kynurenine Pathway in a clinical MDD sample with increased cytokine levels. Methods Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed for 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and their blood was analyzed for tryptophan and its metabolites in the Kynurenine Pathway. The clinical assessments and metabolite measurements were repeated after 12 weeks of “treatment as usual”. Results We did not find significant elevation of Kynurenine plasma markers in patients with a depressive episode compared to healthy controls, despite elevated cytokine levels in the patients. Clinical depression scores were significantly reduced after 12 weeks, but no significant change in the plasma Kynurenine Pathway plasma markers was observed. Conclusion The obtained results do not support the hypothesis that MDD depressive episodes are associated with elevated activity in the Kynurenine Pathway. This suggests that the pathophysiology underlying depressive episodes in common MDD differs from that of interferon induced depression. Our results warrant further study of the interplay between the Kynurenine Pathway and the cytokine activation patterns in these conditions.
M. P. Heyes - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine Pathway Enzymes in Brain
Advances in Experimental Medicine and Biology, 1996Co-Authors: K. Saito, M. P. HeyesAbstract:The Kynurenine Pathway is the metabolic route by which the essential amino acid, L-tryptophan is catabolized to a number of metabolites for excretion and convertion to nicotinamide-containing nucleotides (Bender, 1982). The liver is viewed as the major source of Kynurenine Pathway metabolites in blood and urine. Certain Kynurenine Pathway metabolites are also neuroactive within the central nervous system (CNS), including L-Kynurenine (L-KYN) (Lapin, 1982), kynurenic acid (KYNA), 3-hydroxyKynurenine (Eastman, 1989) and quinolinic acid (QUIN) (Lapin, 1982; Schwarcz et al., 1983; Rios et al, 1991). Accumulations of these neuroactive metabolites have been implicated in a number of neurodegenerative, convulsant and neurologic diseases, including complex partial seizures, HIV-associated neurologic disease, as well as a broad spectrum of inflammatory conditions that result from microbiological infections, autoimmune processes and brain injury (Lapin, 1982; Heyes et al, 1991; Heyes et al., 1992; Stone, 1993). Normally, the concentrations of Kynurenine Pathway metabolites within the CNS are low, and only a few metabolic steps have been demonstrated to occur within the normal brain. While direct conversion of L-tryptophan to QUIN has not been demonstrated in brain from normal animals, direct conversion does occur in brain tissue from 4 days following transient cerebral ischemia or macaques from poliovirus infected spinal cord.
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The Kynurenine Pathway and Neurologic Disease
Advances in Experimental Medicine and Biology, 1996Co-Authors: M. P. HeyesAbstract:Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan — Kynurenine Pathway (Bender, 1982) that selectively injures and kills vulnerable neurons via activation of the N-methyl-D-aspartate class of excitatory amino acid receptors (Stone, 1993). Accumulations of QUIN have been hypothesized to cause a broad spectrum of human neurologic disease.
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Cytokine and Drug Modulation of Kynurenine Pathway Metabolism by Blood Mononuclear Cells
Advances in Experimental Medicine and Biology, 1996Co-Authors: Koshiro Saito, Mitsuru Seishima, Akio Noma, Sanford P. Markey, M. P. HeyesAbstract:Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-Kynurenine (L-KYN) are neuroactive L-tryptophan metabolites that are synthesized via the Kynurenine Pathway. These metabolites accumulate in CNS following immune stimulation (particularly those with inflammatory lesions and monocyte infiltration into the CNS) and are attributed to induction of indoleamine-2,3-dioxygenase (IDO) and other Kynurenine Pathway enzymes (Saito et al., 1993a; Heyes et al., 1992a; 1993).
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Kynurenine Pathway metabolism in the galactosamine model of hepatic injury.
Advances in Experimental Medicine and Biology, 1996Co-Authors: K. Saito, Mitsuru Seishima, Akio Noma, Sanford P. Markey, Yoichi Nagamura, Bonnie J. Quearry, M. P. HeyesAbstract:The mechanisms involved in producing hepatic encephalopathy and hepatic coma are unclear, but include an accumulation of neurotoxic metabolites. Elevated plasma concentrations of aromatic amino acids, including L-tryptophan, are characteristic of hepatic injury (James et al., 1976). Key metabolites of the L-tryptophan-Kynurenine Pathway are neuroactive within the central nervous system. Quinolinic acid (QUIN) is an agonist of N-methyl-D-aspartate receptors and an excitotoxin (Lapin, 1982; Schwarcz et al., 1983; Whetsell et al., 1989) while kynurenic acid (KYNA) is an antagonist of excitatory amino acid receptors and attenuates the excitotoxic effects of QUIN (Foster et al., 1984). L-Kynurenine (L-KYN) is a convulsant (Lapin, 1982), and 3-hydroxyKynurenine may be neurotoxic (Eastman et al, 1989). Therefore, accumulation of neuroactive Kynurenine Pathway metabolites within the brain may be of functional or clinical significance. In addition, while the concentrations of QUIN, KYNA and L-KYN within the CNS are low in neurologically normal subjects and patients with chronic non-inflammatory neurological diseases, substantial increases occur in the CNS of humans and non-human primates with inflammatory neurological conditions, particularly those with inflammatory lesions and monocyte infiltration into the CNS (Heyes et al., 1992). In the present study, we have used systemic injections of galactosamine as a model of acute hepatic injury, with which to evaluate systemic and CNS Kynurenine Pathway responses.
Bruce J Brew - One of the best experts on this subject based on the ideXlab platform.
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Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease.
PLOS ONE, 2015Co-Authors: Simon Jones, Gilles J Guillemin, Chai K. Lim, Josien De Bie, Nunzio F. Franco, Bianca Varney, Gayathri Sundaram, David A. Brown, Bruce J BrewAbstract:The Kynurenine Pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of Kynurenine Pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key Kynurenine Pathway enzymes and the main Kynurenine Pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), Kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of Kynurenine Pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the Kynurenine Pathway (Kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify Kynurenine Pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.
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The Kynurenine Pathway and quinolinic acid: pivotal roles in HIV associated neurocognitive disorders.
FEBS Journal, 2012Co-Authors: Apsara Kandanearatchi, Bruce J BrewAbstract:This brief review will first consider HIV associated neurocognitive disorder followed by the current understanding of its neuropathogenesis. Against this background the role of the Kynurenine Pathway will be detailed. Evidence both direct and indirect will be discussed for involvement of the Kynurenine Pathway at each step in the neuropathogenesis of HIV associated neurocognitive disorder.
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Characterization of the Kynurenine Pathway in human neurons.
Journal of Neuroscience, 2007Co-Authors: Gilles J Guillemin, Karen M. Cullen, Chai K. Lim, George A. Smythe, Brett Garner, Vimal Kapoor, Osamu Takikawa, Bruce J BrewAbstract:The Kynurenine Pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the Kynurenine Pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the Kynurenine Pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of Kynurenine Pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the Kynurenine Pathway in neurons and the first description of the involvement of the Kynurenine Pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.
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Kynurenine Pathway metabolism in human astrocytes.
Advances in Experimental Medicine and Biology, 1999Co-Authors: Gilles J Guillemin, George A. Smythe, Stephen J. Kerr, Patricia J. Armati, Bruce J BrewAbstract:The involvement of astrocytes in Kynurenine Pathway (KP) metabolism is still poorly understood. In the present study, we investigated the ability of human fetal astrocytes in vitro to produce quinolinic and picolinic acids using mass spectrometry. In parallel, we estimated the level of expression of five major KP enzymes using RT-PCR. The results demonstrated that astrocytes express most KP enzymes, except for Kynurenine-hydroxylase. This in vitro study provides novel informations regarding the ability of human fetal astrocytes to degrade L-tryptophan along the KP.
Robert Schwarcz - One of the best experts on this subject based on the ideXlab platform.
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The Kynurenine Pathway and the brain: Challenges, controversies and promises.
Neuropharmacology, 2017Co-Authors: Robert Schwarcz, Trevor W. StoneAbstract:Research on the neurobiology of the Kynurenine Pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that Kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, Kynurenine Pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that Kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain Kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the Kynurenine Pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of Kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
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Cortical Kynurenine Pathway Metabolism: A Novel Target for Cognitive Enhancement in Schizophrenia
Schizophrenia Bulletin, 2010Co-Authors: Ikwunga Wonodi, Robert SchwarczAbstract:The brain concentration of kynurenic acid (KYNA), a metabolite of the Kynurenine Pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the α7 nicotinic acetylcholine receptor (α7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the α7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of Kynurenine Pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, Kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical Kynurenine Pathway metabolism for cognition enhancement in schizophrenia and beyond.
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Histone deacetylase inhibition modulates Kynurenine Pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment.
Journal of Biological Chemistry, 2007Co-Authors: Flaviano Giorgini, Robert Schwarcz, Thomas Möller, Wanda Kwan, Daniel Zwilling, Jennifer L. Wacker, Soyon Hong, Li-chun L. Tsai, Christine S. Cheah, Paolo GuidettiAbstract:The Kynurenine Pathway of tryptophan degradation is hypothesized to play an important role in Huntington disease, a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin. Neurotoxic metabolites of the Kynurenine Pathway, generated in microglia and macrophages, are present at increased levels in the brains of patients and mouse models during early stages of disease, but the mechanism by which Kynurenine Pathway up-regulation occurs in Huntington disease is unknown. Here we report that expression of a mutant huntingtin fragment was sufficient to induce transcription of the Kynurenine Pathway in yeast and that this induction was abrogated by impairing the activity of the histone deacetylase Rpd3. Moreover, numerous genetic suppressors of mutant huntingtin toxicity that are functionally unrelated converged unexpectedly on the Kynurenine Pathway, supporting a critical role for the Kynurenine Pathway in mediating mutant huntingtin toxicity in yeast. Histone deacetylase-dependent regulation of the Kynurenine Pathway was also observed in a mouse model of Huntington disease, in which treatment with a neuroprotective histone deacetylase inhibitor blocked activation of the Kynurenine Pathway in microglia expressing a mutant huntingtin fragment in vitro and in vivo. These findings suggest that a mutant huntingtin fragment can perturb transcriptional programs in microglia, and thus implicate these cells as potential modulators of neurodegeneration in Huntington disease that are worthy of further investigation.
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the Kynurenine Pathway of tryptophan degradation as a drug target
Current Opinion in Pharmacology, 2004Co-Authors: Robert SchwarczAbstract:Abstract In mammalian cells, the essential amino acid tryptophan is degraded primarily by the Kynurenine Pathway, a cascade of enzymatic steps containing several biologically active compounds. Metabolites of this Pathway, collectively termed ‘Kynurenines’, have been shown to be involved in many diverse physiological and pathological processes. In particular, fluctuations in the levels of Kynurenines have discrete effects on the nervous and immune systems. A considerable number of pharmacological tools have recently become available to probe the Kynurenine Pathway experimentally. Some of these ‘kynurenergic’ agents can be envisioned to be of therapeutic value, especially in the treatment of diseases that are associated with impaired Kynurenine Pathway metabolism.
