The kynurenine pathway and inflammation in amyotrophic lateral sclerosis.
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.
Chen
Yiquan
Y
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Stankovic
Roger
R
Cullen
Karen M
KM
Meininger
Vincent
V
Garner
Brett
B
Coggan
Sarah
S
Grant
Ross
R
Brew
Bruce J
BJ
Guillemin
Gilles J
GJ
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000378:metabolism*; D007737:Kynurenine / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D010848:Picolinic Acids / Q000097:blood / Q000134:cerebrospinal fluid; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013116:Spinal Cord / Q000378:metabolism; D014364:Tryptophan / Q000097:blood / Q000134:cerebrospinal fluid
D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010848:Picolinic Acids; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid; C030614:picolinic acid