The Kynurenine Pathway and Inflammation in Amyotro

Authors: Yiquan Chen Roger Stankovic Karen M Cullen Vincent Meininger Brett Garner Sarah Coggan Ross Grant Bruce J Brew Gilles J Guillemin

Publish Date: 2009/11/18

Volume: 18, Issue: 2, Pages: 132-142

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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 23dioxygenase 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 antigenDR HLADR in sections of brain and spinal cord from ALS patients There were significantly increased levels of CSF and serum TRP P  00001 KYN P  00001 and QUIN P  005 and decreased levels of serum PIC P  005 in ALS samples There was a significant increase in activated microglia expressing HLADR P  00001 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 inflammationdriven excitotoxicchelation defective mechanism in ALS which may be amenable to inhibitors of the KPThis 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 NIAAAgrant no R01AAA01272508 Sydney South Western Area Health Service SSWAHS

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