Tryptophan metabolism and oxidative stress in patients with Huntington's disease.
Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction.
Stoy
N
N
Royal Hospital for Neuro-Disability, Putney, London, UK.
Mackay
G M
GM
Forrest
C M
CM
Christofides
J
J
Egerton
M
M
Stone
T W
TW
Darlington
L G
LG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; 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; D014364:Tryptophan / Q000097:blood / Q000172:deficiency / Q000378:metabolism*
D000447:Aldehydes; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D007737:Kynurenine; D008315:Malondialdehyde; D019798:Neopterin; D014364:Tryptophan; C027576:4-hydroxy-2-nonenal