Document Detail


The kynurenine pathway and inflammation in amyotrophic lateral sclerosis.
MedLine Citation:
PMID:  19921535     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yiquan Chen; Roger Stankovic; Karen M Cullen; Vincent Meininger; Brett Garner; Sarah Coggan; Ross Grant; Bruce J Brew; Gilles J Guillemin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-18
Journal Detail:
Title:  Neurotoxicity research     Volume:  18     ISSN:  1476-3524     ISO Abbreviation:  Neurotox Res     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-06-07     Completed Date:  2010-09-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100929017     Medline TA:  Neurotox Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  132-42     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
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MeSH Terms
Descriptor/Qualifier:
Adult
Amyotrophic Lateral Sclerosis / blood,  cerebrospinal fluid,  complications,  metabolism*
Brain / metabolism
Female
HLA-DR Antigens / metabolism
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Inflammation / blood,  cerebrospinal fluid,  complications,  metabolism*
Kynurenine* / blood,  cerebrospinal fluid
Male
Middle Aged
Picolinic Acids / blood,  cerebrospinal fluid
Quinolinic Acid / blood,  cerebrospinal fluid,  metabolism
Signal Transduction / immunology*
Spinal Cord / metabolism
Tryptophan / blood,  cerebrospinal fluid
Chemical
Reg. No./Substance:
0/HLA-DR Antigens; 0/Picolinic Acids; 343-65-7/Kynurenine; 73-22-3/Tryptophan; 89-00-9/Quinolinic Acid; 98-98-6/picolinic acid; EC 1.13.11.42/Indoleamine-Pyrrole 2,3,-Dioxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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