Understanding the Roles of the Kynurenine Pathway in Multiple Sclerosis Progression

The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of nicotinamide adenine dinucleotide (NAD+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease, schizophrenia, Huntington's disease and brain tumours. However, the KP remains a relatively new topic for the field of multiple sclerosis (MS). Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients. This review summarizes the known relationships between the KP and MS.

[1]  B. Brew,et al.  Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease , 2009, Journal of Neuroinflammation.

[2]  Gilles J. Guillemin,et al.  The Excitotoxin Quinolinic Acid Induces Tau Phosphorylation in Human Neurons , 2009, PloS one.

[3]  B. Brew,et al.  Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons , 2009, Neurotoxicity Research.

[4]  I. Efimov,et al.  Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase. , 2009, Biochemical Society transactions.

[5]  H. Weiner,et al.  The challenge of multiple sclerosis: How do we cure a chronic heterogeneous disease? , 2009, Annals of neurology.

[6]  H. Ball,et al.  Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. , 2009, The international journal of biochemistry & cell biology.

[7]  B. Brew,et al.  Effects of Kynurenine Pathway Metabolites on Intracellular NAD+ Synthesis and Cell Death in Human Primary Astrocytes and Neurons , 2009, International journal of tryptophan research : IJTR.

[8]  G. Guillemin,et al.  Kynurenine Pathway Metabolites in Humans: Disease and Healthy States , 2009, International journal of tryptophan research : IJTR.

[9]  S. Amor,et al.  Axonal loss and gray matter pathology as a direct result of autoimmunity to neurofilaments , 2008, Neurobiology of Disease.

[10]  K. Selmaj,et al.  Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism , 2008, Journal of Neuroimmunology.

[11]  Gilles J Guillemin,et al.  Characterization of the Kynurenine Pathway in Human Neurons , 2007, The Journal of Neuroscience.

[12]  B. Brew,et al.  Effect of quinolinic acid on gene expression in human astrocytes: Implications for Alzheimer's disease , 2007 .

[13]  B. Brew,et al.  Characterization of the kynurenine pathway in human oligodendrocytes , 2007 .

[14]  S. Komoly,et al.  The involvement of mitochondria in the pathogenesis of multiple sclerosis , 2007, Journal of Neuroimmunology.

[15]  I. Bechmann,et al.  IDO expression in the brain: a double-edged sword , 2007, Journal of Molecular Medicine.

[16]  J. Toldi,et al.  Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders , 2007, Journal of the Neurological Sciences.

[17]  Hans Lassmann,et al.  The Immunopathology of Multiple Sclerosis: An Overview , 2007, Brain pathology.

[18]  W. Turski,et al.  Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis , 2007, Journal of Neural Transmission.

[19]  Álvaro González,et al.  Bimodal effect of nitric oxide in the enzymatic activity of indoleamine 2,3-dioxygenase in human monocytic cells. , 2006, Immunology letters.

[20]  Hans Lassmann,et al.  Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. , 2006, Brain : a journal of neurology.

[21]  D. Tagle,et al.  Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family. , 2006, Gene.

[22]  V. Meininger,et al.  Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis , 2006, Neurodegenerative Diseases.

[23]  M. Salter,et al.  NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury , 2005, Nature.

[24]  I. Bechmann,et al.  Indolamine 2,3‐dioxygenase is expressed in the CNS and down‐regulates autoimmune inflammation , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  P. Klivényi,et al.  Kynurenine metabolism in multiple sclerosis , 2005, Acta neurologica Scandinavica.

[26]  W. Turski,et al.  Demonstration of Kynurenine Aminotransferases I and II and Characterization of Kynurenic Acid Synthesis in Oligodendrocyte Cell Line (OLN-93) , 2005, Neurochemical Research.

[27]  B. Brew,et al.  Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex , 2005, Journal of Neuroinflammation.

[28]  B. Kepplinger,et al.  Age-Related Increase of Kynurenic Acid in Human Cerebrospinal Fluid – IgG and β2-Microglobulin Changes , 2005, Neurosignals.

[29]  R. Schwarcz,et al.  Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice , 2004, Molecular and Cellular Biology.

[30]  Daniel Offen,et al.  The role of oxidative stress in the pathogenesis of multiple sclerosis: The need for effective antioxidant therapy , 2004, Journal of Neurology.

[31]  B. Brew,et al.  A&bgr;1-42 induces production of quinolinic acid by human macrophages and microglia , 2003, Neuroreport.

[32]  Max S. Cynader,et al.  Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis , 2003, Journal of Neuroimmunology.

[33]  T. Olsson,et al.  Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis , 2003, Journal of Neuroimmunology.

[34]  B. Trapp,et al.  Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease , 2003, Journal of the Neurological Sciences.

[35]  D. Munn,et al.  Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division , 2002, Immunology.

[36]  G. Giovannoni,et al.  Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients , 2002, Neuroscience Letters.

[37]  U. Grohmann,et al.  T cell apoptosis by tryptophan catabolism , 2002, Cell Death and Differentiation.

[38]  Gerhard Opelz,et al.  Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells , 2002, The Journal of experimental medicine.

[39]  J. Ward,et al.  Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis , 2002, Journal of Neuroimmunology.

[40]  D. Souza,et al.  Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes , 2002, Neurochemistry International.

[41]  K. Blennow,et al.  Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia , 2001, Neuroscience Letters.

[42]  B. Brew,et al.  Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection , 2001, Journal of neurochemistry.

[43]  S. Mandel,et al.  Gene expression analysis in N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice model of Parkinson's disease using cDNA microarray: effect of R‐apomorphine , 2001, Journal of neurochemistry.

[44]  C. Brosnan,et al.  Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. , 2001, The American journal of pathology.

[45]  W. Cammer Oligodendrocyte killing by quinolinic acid in vitro , 2001, Brain Research.

[46]  L. Massacesi,et al.  Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis , 2001, Neuroscience.

[47]  D. Bates Multiple Sclerosis: the Questions You Have—the Answers You Need. , 2000 .

[48]  H. Kim,et al.  Enhanced expression of constitutive and inducible forms of nitric oxide synthase in autoimmune encephalomyelitis. , 2000, Journal of veterinary science.

[49]  D. Souza,et al.  Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain , 2000, Neuroreport.

[50]  R. Schwarcz,et al.  3‐Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum , 1999, The European journal of neuroscience.

[51]  V. Perry,et al.  Axon damage and repair in multiple sclerosis. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[52]  F. Moroni,et al.  Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. , 1999, European journal of pharmacology.

[53]  D. Munn,et al.  Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism , 1999, The Journal of experimental medicine.

[54]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[55]  R. Albin,et al.  Chronic Administration of Quinolinic Acid in the Rat Striatum Causes Spatial Learning Deficits in a Radial Arm Water Maze Task , 1998, Experimental Neurology.

[56]  B. Brew,et al.  Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex , 1998, AIDS.

[57]  J. Mcdonald,et al.  Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity , 1998, Nature Medicine.

[58]  B. Brew,et al.  Quinolinic Acid Production by Macrophages Stimulated with IFN-γ, TNF-α, and IFN-α , 1997 .

[59]  E. Major,et al.  Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. , 1997, The Biochemical journal.

[60]  R. Miledi,et al.  Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[61]  V. Perry,et al.  Axonal damage in acute multiple sclerosis lesions. , 1997, Brain : a journal of neurology.

[62]  E. Benveniste Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis , 1997, Journal of Molecular Medicine.

[63]  C. Colton,et al.  Activated human microglia produce the excitotoxin quinolinic acid , 1997, Neuroreport.

[64]  N. Nishiyama,et al.  Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Christian Steinhäuser,et al.  News on glutamate receptors in glial cells , 1996, Trends in Neurosciences.

[66]  R. Sandyk Tryptophan availability and the susceptibility to stress in multiple sclerosis: a hypothesis. , 1996, The International journal of neuroscience.

[67]  O. Bagasra,et al.  Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[68]  O. H. Viveros,et al.  Neurotoxin Quinolinic Acid Is Selectively Elevated in Spinal Cords of Rats with Experimental Allergic Encephalomyelitis , 1995, Journal of neurochemistry.

[69]  G. Reynolds,et al.  Increased Concentrations of the Neurotoxin 3‐Hydroxykynurenine in the Frontal Cortex of HIV‐1‐Positive Patients , 1995, Journal of neurochemistry.

[70]  R. Stocker,et al.  Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferon-gamma primed mononuclear phagocytes. , 1994, The Journal of biological chemistry.

[71]  O. Devinsky,et al.  Kynurenine Pathway Metabolites in Cerebrospinal Fluid and Serum in Complex Partial Seizures , 1994, Epilepsia.

[72]  W. Engelhardt,et al.  Interleukin-2, soluble interleukin-2-receptor, neopterin,l-tryptophan and β2-microglobulin levels in CSF and serum of patients with relapsing-remitting or chronic-progressive multiple sclerosis , 1993, Journal of Neurology.

[73]  T. Stone,et al.  Neuropharmacology of quinolinic and kynurenic acids. , 1993, Pharmacological reviews.

[74]  M. Beal,et al.  Kynurenine pathway abnormalities in Parkinson's disease , 1992, Neurology.

[75]  E. Major,et al.  Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. , 1992, The Biochemical journal.

[76]  D. Monaghan,et al.  Quinolinate differentiates between forebrain and cerebellar NMDA receptors. , 1991, European journal of pharmacology.

[77]  M. Plotkine,et al.  Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: Behavioral and histological evaluation , 1990, Neuroscience Letters.

[78]  T. Guilarte,et al.  The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine , 1990, Neurochemical Research.

[79]  O. Takikawa,et al.  IFN-gamma is the inducer of indoleamine 2,3-dioxygenase in allografted tumor cells undergoing rejection. , 1990, Journal of immunology.

[80]  E. Werner,et al.  Immune-mediated mechanisms in multiple sclerosis , 1990, Journal of Neurology.

[81]  G. Reynolds,et al.  INCREASED BRAIN 3-HYDROXYKYNURENINE IN HUNTINGTON'S DISEASE , 1989, The Lancet.

[82]  T. Guilarte,et al.  Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line , 1989, Brain Research.

[83]  C. Grossman,et al.  Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. , 1988, European journal of pharmacology.

[84]  O. Hayaishi,et al.  Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. , 1986, The Journal of biological chemistry.

[85]  R. Schwarcz,et al.  Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid , 1984, Neuroscience Letters.

[86]  R. Schwarcz,et al.  On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds , 1983, Neuropharmacology.

[87]  R. Schwarcz,et al.  Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. , 1983, Science.

[88]  T. Stone,et al.  An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid , 1982, Brain Research.

[89]  T. Stone,et al.  Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. , 1981, European journal of pharmacology.

[90]  R. Mutani,et al.  Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases. , 1979, Journal of neurology, neurosurgery, and psychiatry.

[91]  B. Brew,et al.  Quinolinic acid is produced by macrophages stimulated by platelet activating factor, Nef and Tat , 2011, Journal of NeuroVirology.

[92]  B. Brew,et al.  Involvement of quinolinic acid in aids dementia complex , 2009, Neurotoxicity Research.

[93]  P. Puccetti,et al.  Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host. , 2009, Microbes and infection.

[94]  R. Dantzer,et al.  Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. , 2009, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[95]  J. Bergquist,et al.  Kynurenines, redox disturbances and neurodegeneration in multiple sclerosis. , 2007, Journal of neural transmission. Supplementum.

[96]  B. Kepplinger,et al.  Age-related increase of kynurenic acid in human cerebrospinal fluid - IgG and beta2-microglobulin changes. , 2005, Neuro-Signals.

[97]  B. Brew,et al.  Expression of indoleamine 2,3‐dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons , 2005, Glia.

[98]  B. Brew,et al.  Expression of the kynurenine pathway enzymes in human microglia and macrophages. , 2003, Advances in experimental medicine and biology.

[99]  E. Ragazzi,et al.  Kynurenine pathway enzymes in different species of animals. , 2003, Advances in experimental medicine and biology.

[100]  D. Pitt,et al.  Glutamate excitotoxicity in a model of multiple sclerosis , 2000, Nature Medicine.

[101]  ichard,et al.  AXONAL TRANSECTION IN THE LESIONS OF MULTIPLE SCLEROSIS , 1998 .

[102]  B. Brew,et al.  Quinolinic acid production by macrophages stimulated with IFN-gamma, TNF-alpha, and IFN-alpha. , 1997, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[103]  D. Fuchs,et al.  Serum tryptophan, kynurenine, and neopterin in patients with Guillain-Barre-syndrome (GBS) and multiple sclerosis (MS). , 1996, Advances in experimental medicine and biology.

[104]  M. Heyes The Kynurenine Pathway and Neurologic Disease , 1996 .

[105]  M. Heyes The kynurenine pathway and neurologic disease. Therapeutic strategies. , 1996, Advances in experimental medicine and biology.

[106]  G. Reynolds,et al.  Neurochemical-clinical correlates in Huntington's disease--applications of brain banking techniques. , 1993, Journal of neural transmission. Supplementum.

[107]  S. Markey,et al.  Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. , 1992, The Biochemical journal.