Tryptophan metabolism and oxidative stress in patients with chronic brain injury.
The kynurenine pathway generates the excitotoxic N-methyl-d-aspartate receptor agonist, quinolinic acid and the glutamate antagonist, kynurenic acid, as well as free-radical generators. We investigated the status of the pathway following severe brain injury sustained at least 1 year previously in 15 patients compared with controls. At baseline, patients with brain injury showed increased levels of neopterin, erythrocyte sedimentation rate, C-reactive protein and peroxidation products in the blood compared with controls, indicating persistent inflammation and oxidative stress. At baseline and following tryptophan depletion, more tryptophan was converted to kynurenine in patients than controls, but less kynurenine was converted into the neuroprotectant, kynurenic acid. This suggests that neuroprotection by kynurenic acid may be inadequate in brain-damaged patients even many years after injury. On tryptophan loading, patients metabolized more kynurenine into kynurenic acid than controls, a process which may be neuroprotective. In addition, lower levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in patients after tryptophan loading should be protective since these compounds generate free radicals. The results suggest that for brain-damaged patients, increased activation of the kynurenine pathway, oxidative stress and raised levels of inflammation continue many years after the original insult, possibly contributing to the continuing cerebral dysfunction in these patients.
Mackay
G M
GM
Institute of Biomedical and Life Sciences, University of Glasgow, and Royal Hospital for Neuro-disability, London, UK.
Forrest
C M
CM
Stoy
N
N
Christofides
J
J
Egerton
M
M
Stone
T W
TW
Darlington
L G
LG
D000328:Adult; D000368:Aged; D001930:Brain Injuries / Q000178:diet therapy / Q000378:metabolism* / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D019798:Neopterin / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D014364:Tryptophan / Q000172:deficiency / Q000378:metabolism*
D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D007737:Kynurenine; D019798:Neopterin; D014364:Tryptophan