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The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

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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.

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Acknowledgements

This study was funded by the Motor Neuron Disease Research Institute Association (Australia). The NSW Tissue Resource Centre is supported by The University of Sydney, Schizophrenia Research Institute, National Institutes on Alcohol Abuse and Alcoholism (NIAAA-grant no: R01AAA01272508), Sydney South Western Area Health Service (SSWAHS).

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Authors and Affiliations

  1. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Yiquan Chen, Sarah Coggan, Ross Grant & Gilles J. Guillemin

  2. St. Vincent’s Centre for Applied Medical Research, Darlinghurst, 2010, Australia

    Bruce J. Brew & Gilles J. Guillemin

  3. Department of Neurology, St. Vincent’s Hospital, Darlinghurst, 2010, Australia

    Bruce J. Brew

  4. Anatomy and Histology, School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia

    Roger Stankovic & Karen M. Cullen

  5. Centre for SLA, Hôpital Pitié-Salpêtrière, APHP, Paris, France

    Vincent Meininger

  6. Australasian Research Institute, Sydney Adventist Hospital, Sydney, NSW, 2076, Australia

    Ross Grant

  7. Prince of Wales Medical Research Institute, Randwick, NSW, 2031, Australia

    Brett Garner

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  1. Yiquan Chen
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  2. Roger Stankovic
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Correspondence to Gilles J. Guillemin.

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Chen, Y., Stankovic, R., Cullen, K.M. et al. The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis. Neurotox Res 18, 132–142 (2010). https://doi.org/10.1007/s12640-009-9129-7

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