The kynurenine pathway and inflammation in amyotrophic lateral sclerosis
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. 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 chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ALS patients have higher CSF and serum levels of tryptophan, kynurenine, and quinolinic acid, and lower serum picolinic acid, than controls.
“In ALS patients, there were higher levels of CSF and serum tryptophan, kynurenine, and quinolinic acid, and decreased serum picolinic acid”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Chen et al., 2010
The kynurenine pathway is impaired in ALS patients.
“Similar to that in HD patients, the kynurenine pathway is also impaired in ALS.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Chen et al., 2010
ALS patients show greater microglial inflammation and increased neuronal and microglial expression of indoleamine 2,3-dioxygenase and quinolinic acid in motor cortex and spinal cord tissues.
“there was higher microglial inflammation and increased neuronal and microglial expression of indoleamine 2,3-dioxygenase and quinolinic acid in the motor cortex and spinal cord tissues from ALS patients”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Chen et al., 2010
Cites
Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., Deng, H.-X., et al. (1993) · Nature · doi:10.1038/362059a0 · Cited by 7,062 · see citing works
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000) · Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders · doi:10.1080/146608200300079536 · Cited by 5,433 · see citing works
Prevention of Allogeneic Fetal Rejection by Tryptophan Catabolism
Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I. E., Conway, S. J., Marshall, B., Brown, C. C., & Mellor, A. L. (1998) · Science · doi:10.1126/science.281.5380.1191 · Cited by 2,589 · see citing works
A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis
Bensimon, G., Lacomblez, L., & Meininger, V. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403033300901 · Cited by 2,239 · see citing works
Self-citationUNRAVELING THE MECHANISMS INVOLVED IN MOTOR NEURON DEGENERATION IN ALS
Bruijn, L. I., Miller, T. M., & Cleveland, D. W. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144244 · Cited by 1,371 · see citing works
Dose-ranging study of riluzole in amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis/Riluzole Study Group II, Lacomblez, L., Bensimon, G., Meininger, V., Leigh, P. N., & Guillet, P. (1996) · The Lancet · doi:10.1016/s0140-6736(96)91680-3 · Cited by 1,303 · see citing works
Self-citationAggregation and Motor Neuron Toxicity of an ALS-Linked SOD1 Mutant Independent from Wild-Type SOD1
Bruijn, L. I., Houseweart, M. K., Kato, S., Anderson, K. L., Anderson, S., Ohama, E., Reaume, A. G., Scott, R. W., & Cleveland, D. W. (1998) · Science · doi:10.1126/science.281.5384.1851 · Cited by 1,231 · see citing works
Frumento, G., Rotondo, R., Tonetti, M., Damonte, G., Benatti, U., & Ferrara, G. B. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020121 · Cited by 1,133 · see citing works
Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., & Prendergast, G. C. (2005) · Nature Medicine · doi:10.1038/nm1196 · Cited by 1,064 · see citing works
Microglia as neuroprotective, immunocompetent cells of the CNS
Streit, W. J. (2002) · Glia · doi:10.1002/glia.10154 · Cited by 919 · see citing works
Perkins, M. N., & Stone, T. W. (1982) · Brain Research · doi:10.1016/0006-8993(82)91048-4 · Cited by 849 · see citing works
Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism
Fukui, S., Schwarcz, R. M., Rapoport, S. I., Takada, Y., & Smith, Q. R. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb03460.x · Cited by 765 · see citing works
Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS
Stone, T. W., & Perkins, M. N. (1981) · European Journal of Pharmacology · doi:10.1016/0014-2999(81)90587-2 · Cited by 751 · see citing works
Monitoring tryptophan metabolism in chronic immune activation
Schröcksnadel, K., Wirleitner, B., Winkler, C., & Fuchs, D. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2005.06.013 · Cited by 551 · cited 2× · see citing works
“method used here is a modification of a published protocol (Schrocksnadel et al. 2006). CSF and serum samples were Neurotox Res (2010) 18:132–142 133”
MethodKynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection
Guillemin, G. J., Kerr, S. J., Smythe, G. A., Smith, D. G., Kapoor, V., Armati, P. J., Croitoru‐Lamoury, J., & Brew, B. J. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00498.x · Cited by 541 · see citing works
Self-citationCurrent hypotheses for the underlying biology of amyotrophic lateral sclerosis
Rothstein, J. D. (2009) · Annals of Neurology · doi:10.1002/ana.21543 · Cited by 510 · see citing works
Inflammatory processes in amyotrophic lateral sclerosis
McGeer, P. L., & McGeer, E. G. (2002) · Muscle & Nerve · doi:10.1002/mus.10191 · Cited by 470 · see citing works
Human macrophages convert l -tryptophan into the neurotoxin quinolinic acid
Heyes, M. P., Saito, K., & Markey, S. P. (1992) · Biochemical Journal · doi:10.1042/bj2830633 · Cited by 448 · see citing works
Watanabe, M., Dykes‐Hoberg, M., Culotta, V., Price, D. L., Wong, P. C., & Rothstein, J. D. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0443 · Cited by 432 · see citing works
Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase.
Takikawa, O., Yoshida, R., Kido, R., et al. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)35696-x · Cited by 377 · see citing works
Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus
Guillemin, G., Brew, B., Noonan, C. E., Takikawa, O., & Cullen, K. (2005) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2005.00655.x · Cited by 331 · see citing works
Self-citationCharacterization of the Kynurenine Pathway in Human Neurons
Guillemin, G. J., Cullen, K. M., Lim, C. K., Smythe, G. A., Garner, B., Kapoor, V., Takikawa, O., & Brew, B. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4101-07.2007 · Cited by 325 · see citing works
Self-citationMolecular and cellular pathways of neurodegeneration in motor neurone disease
Shaw, P. J. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.048652 · Cited by 311 · see citing works
Tryptophan degradation and immune activation in Alzheimer's disease
Widner, B., Leblhuber, F., Walli, J., Tilz, G. P., Demel, U., & Fuchs, D. (2000) · Journal of Neural Transmission · doi:10.1007/s007020050029 · Cited by 287 · see citing works
Human microglia convert l -tryptophan into the neurotoxin quinolinic acid
Heyes, M. P., Achim, C. L., Wiley, C. A., Major, E. O., Saito, K., & Markey, S. P. (1996) · Biochemical Journal · doi:10.1042/bj3200595 · Cited by 260 · see citing works
Lyons, T. J., Liu, H., Goto, J. J., Nersissian, A. M., Roe, J. A., Graden, J. A., Café, C., Ellerby, L., Bredesen, D. E., Gralla, E. B., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.22.12240 · Cited by 183 · see citing works
Yoshida, R., & Hayaishi, O. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.8.3998 · Cited by 182 · see citing works
Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes
Guillemin, G. J., Croitoru‐Lamoury, J., Dormont, D., Armati, P. J., & Brew, B. J. (2003) · Glia · doi:10.1002/glia.10175 · Cited by 176 · see citing works
Self-citationIncreased neopterin production and tryptophan degradation in advanced Parkinson's disease.
Widner, B., Leblhuber, F., & Fuchs, D. (2002) · Journal of Neural Transmission · doi:10.1007/s007020200014 · Cited by 171 · see citing works
Quinolinic acid induces oxidative stress in rat brain synaptosomes
Santamarı́a, A., Galván‐Arzate, S., Lisý, V., Ali, S. F., Duhart, H. M., Osorio‐Rico, L., Rı́os, C., & Sut'astný, F. (2001) · Neuroreport · doi:10.1097/00001756-200103260-00049 · Cited by 152 · see citing works
Expression of a system L neutral amino acid transporter at the blood–brain barrier
Matsuo, H., Tsukada, S., Nakata, T., Chairoungdua, A., Kim, D. K., Ho, S., Inatomi, J., Yorifuji, H., Fukuda, J., Endou, H., et al. (2000) · Neuroreport · doi:10.1097/00001756-200011090-00021 · Cited by 147 · see citing works
Involvement of quinolinic acid in aids dementia complex
Guillemin, G. J., Kerr, S. J., & Brew, B. J. (2005) · Neurotoxicity Research · doi:10.1007/bf03033781 · Cited by 135 · see citing works
Self-citationSalter, M., & Pogson, C. I. (1985) · Biochemical Journal · doi:10.1042/bj2290499 · Cited by 134 · see citing works
Cytoskeletal Anchoring of GLAST Determines Susceptibility to Brain Damage
Sullivan, S. M., Lee, A., Björkman, S. T., Miller, S. M., Sullivan, R. K. P., Poronnik, P., Colditz, P. B., & Pow, D. V. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704152200 · Cited by 128 · see citing works
Bosco, M. C., Rapisarda, A., Massazza, S., Melillo, G., Young, H. A., & Varesio, L. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.6.3283 · Cited by 121 · see citing works
Owe‐Young, R., Webster, N. L., Mukhtār, M., Pomerantz, R. J., Smythe, G. A., Walker, D. W., Armati, P. J., Crowe, S. M., & Brew, B. J. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05241.x · Cited by 112 · see citing works
Self-citationZhang, H., Andrekopoulos, C., Joseph, J., Chandran, K., Karoui, H., Crow, J. P., & Kalyanaraman, B. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302051200 · Cited by 108 · see citing works
Guillemin, G. J., Smith, D. G., Kerr, S. J., Smythe, G. A., Kapoor, V., Armati, P. J., & Brew, B. J. (2000) · Redox Report · doi:10.1179/135100000101535375 · Cited by 108 · see citing works
Self-citationImplications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis
Guillemin, G. J., Meininger, V., & Brew, B. J. (2005) · Neurodegenerative Diseases · doi:10.1159/000089622 · Cited by 105 · cited 3× · see citing works
“Recent studies have bridged a direct association between the KP and ALS ( Guillemin et al. 2005a ).”
BackgroundInfluentialSelf-citationSmythe, G. A., Braga, O., Brew, B. J., Grant, R., Guillemin, G. J., Kerr, S. J., & Walker, D. W. (2002) · Analytical Biochemistry · doi:10.1006/abio.2001.5490 · Cited by 101 · see citing works
Self-citationNagano, S., Satoh, M., Sumi, H., Fujimura, H., Tohyama, C., Yanagihara, T., & Sakoda, S. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01512.x · Cited by 101 · see citing works
Kynurenine metabolism in plasma and in red blood cells in Parkinson's disease
Hartai, Z., Klivènyi, P., Janáky, T., Penke, B., László, A., & Vécsei, L. (2005) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2005.07.006 · Cited by 98 · see citing works
Transport of Tryptophan into Brain from the Circulating, Albumin‐Bound Pool in Rats and in Rabbits
Pardridge, W. M., & Fierer, G. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb02345.x · Cited by 92 · see citing works
Beninger, R. J., Colton, A. M., Ingles, J. L., Jhamandas, K. H., & Boegman, R. J. (1994) · Neuroscience · doi:10.1016/0306-4522(94)90438-3 · Cited by 87 · see citing works
Tryptophan Loading Induces Oxidative Stress
Forrest, C. M., Mackay, G., Stoy, N. S., Egerton, M., Christofides, J. A., Stone, T. W., & Darlington, L. G. (2004) · Free Radical Research · doi:10.1080/10715760400011437 · Cited by 84 · see citing works
Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites
Jhamandas, K. H., Boegman, R. J., Beninger, R. J., & Bialik, M. (1990) · Brain Research · doi:10.1016/0006-8993(90)90826-w · Cited by 80 · see citing works
Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis
Iłżecka, J., Kocki, T., Stelmasiak, Z., & Turski, W. (2003) · Acta Neurologica Scandinavica · doi:10.1034/j.1600-0404.2003.00076.x · Cited by 75 · see citing works
Smith, A. P., & Lee, N. M. (2007) · Amyotrophic Lateral Sclerosis · doi:10.1080/17482960701249241 · Cited by 65 · see citing works
Fernandez‐Pol, J. A., Klos, D. J., & Hamilton, P. D. (2002) · PubMed · Cited by 52 · see citing works
Brooks, B. R. (2009) · Annals of Neurology · doi:10.1002/ana.21544 · Cited by 51 · see citing works
Cockhill, J., Jhamandas, K. H., Boegman, R. J., et al. (1992) · Brain Research · doi:10.1016/0006-8993(92)90852-z · Cited by 40 · see citing works
Blasi, E., Mazzolla, R., Pitzurra, L., Barluzzi, R., & Bistoni, F. (1993) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.37.11.2422 · Cited by 32 · see citing works
Antitumor Activity of Picolinic Acid in CBA/J Mice 2 3
Leuthauser, S. W. C., Oberley, L. W., & Oberley, T. D. (1982) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/68.1.123 · Cited by 31 · see citing works
Kalisch, B. E., Jhamandas, K. H., Boegman, R. J., & Beninger, R. J. (1994) · Brain Research · doi:10.1016/0006-8993(94)90504-5 · Cited by 30 · see citing works
Tryptophan administration induces oxidative stress in brain cortex of rats
Feksa, L. R., Latini, A., Rech, V. C., Feksa, P. B., Koch, G. D. W., do Amaral, M. F. A., Leipnitz, G., Dutra‐Filho, C. S., Wajner, M., & Wannmacher, C. M. D. (2008) · Metabolic Brain Disease · doi:10.1007/s11011-008-9087-4 · Cited by 26 · see citing works
Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acid
Jhamandas, K. H., Boegman, R. J., Beninger, R. J., et al. (1998) · Amino Acids · doi:10.1007/bf01345272 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
Kynurenines in the CNS: recent advances and new questions
Vécsei, L., Szalárdy, L., Fülöp, F., & Toldi, J. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3793 · Cited by 641 · see citing works
Quinolinic acid: an endogenous neurotoxin with multiple targets
Lugo-Huitrón, R., Ugalde Muñiz, P., Pineda, B., Pedraza-Chaverrí, J., Ríos, C., & Pérez-de la Cruz, V. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/104024 · Cited by 394 · see citing works
Lovelace, M. D., Varney, B., Sundaram, G., Lennon, M. J., Lim, C. K., Jacobs, K., Guillemin, G. J., & Brew, B. J. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.024 · Cited by 393 · see citing works
Self-citationBay-Richter, C., Linderholm, K. R., Lim, C. K., Samuelsson, M., Träskman-Bendz, L., Guillemin, G. J., Erhardt, S., & Brundin, L. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.07.012 · Cited by 304 · see citing works
Self-citationInvolvement of the kynurenine pathway in the pathogenesis of Parkinson's disease
Lim, C. K., Fernández-Gomez, F. J., Braidy, N., Estrada, C., Costa, C., Costa, S., Bessede, A., Fernandez-Villalba, E., Zinger, A., Herrero, M. T., et al. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.009 · Cited by 159 · see citing works
Self-citationTryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders
Li, D., Yu, S., Long, Y., Shi, A., Deng, J., Ma, Y., Wen, J., Li, X., Liu, S., Zhang, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.985378 · Cited by 129 · see citing works
Kynurenic Acid Levels are Increased in the CSF of Alzheimer’s Disease Patients
González-Sánchez, M., Jiménez, J., Narváez, A., Antequera, D., Llamas-Velasco, S., Martín, A. H.-S., Molina Arjona, J. A., López de Munain, A., Lleó Bisa, A., Marco, M.-P., et al. (2020) · Biomolecules · doi:10.3390/biom10040571 · Cited by 84 · see citing works
- Authors
- Chen, Y., Stankovic, R., Cullen, K. M., Meininger, V., Garner, B., Coggan, S., Grant, R., Brew, B. J., & Guillemin, G. J.
- Affiliations
- UNSW Sydney (AU)
- The University of Sydney (AU)
- Assistance Publique – Hôpitaux de Paris (FR)
- Neuroscience Research Australia (AU)
- Sydney Adventist Hospital (AU)
- St Vincent's Hospital Sydney (AU)
- Corresponding author
- Guillemin, Gilles J.
- ORCID
- Venue
- Neurotoxicity Research
- Published
- 2009-11-18
- Volume
- 18
- Issue
- 2
- Pages
- 132-142
- ISSN
- 1029-8428 (ISSN-L)
- 1476-3524
- OpenAlex
- W2018021845
- Cited by
- 141
- References
- 56
- Citations by year
- 2026: 12 · 2025: 3 · 2024: 4 · 2023: 10 · 2022: 9 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 6 · 2017: 5 · 2016: 11 · 2015: 15 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurotoxicity Research (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyotrophic lateral sclerosis, kynurenine pathway, neuroinflammation, tryptophan catabolism, quinolinic acid, picolinic acid, indoleamine 2,3-dioxygenase, HLA-DR, microglial activation, excitotoxicity, cerebrospinal fluid biomarkers, spinal cord, motor cortex
- MeSH terms
- Adult, Amyotrophic Lateral Sclerosis, Brain, Female, HLA-DR Antigens, Humans, Inflammation, Kynurenine, Male, Middle Aged, Picolinic Acids, Spinal Cord, Tryptophan, Signal Transduction, Quinolinic Acid, Indoleamine-Pyrrole 2,3,-Dioxygenase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
