6-Chloro-D,L-tryptophan, 4-chloro-3-hydroxyanthranilate and dexamethasone attenuate quinolinic acid accumulation in brain and blood following systemic immune activation.
Accumulations of the neurotoxin quinolinic acid (QUIN) occur in the brain and blood following immune activation and are attributed to increased metabolism of L-tryptophan through the kynurenine pathway. Systemic administration of 4-chloro-3-hydroxyanthranilate (an inhibitor of 3-hydroxyanthranilate-3,4-dioxygenase), 6-chloro-D,L-tryptophan (a substrate of the kynurenine pathway) and dexamethasone (an anti-inflammatory agent) attenuated the accumulation of QUIN in the brain and blood following systemic pokeweed mitogen administration to mice. 6-Chloro-D,L-tryptophan and dexamethasone also attenuated the increases in brain and lung indoleamine-2,3-dioxygenase activity and elevations in plasma L-kynurenine levels. We conclude that QUIN formation can be modified by drugs which act at different levels of the cascade of events that link immune stimulation to increased kynurenine pathway metabolism.
Saito
K
K
Section on Analytical Biochemistry, National Institute of Mental Health, Bethesda, MD 20892.
Markey
S P
SP
Heyes
M P
MP
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D007107:Immune System / Q000187:drug effects / Q000502:physiology*; D007737:Kynurenine / Q000097:blood / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011043:Pokeweed Mitogens / Q000494:pharmacology; D017378:Quinolinic Acid / Q000097:blood* / Q000378:metabolism*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000378:metabolism
D011043:Pokeweed Mitogens; C026380:6-chlorotryptophan; D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; D007737:Kynurenine; D003907:Dexamethasone; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid