Effects of 540C91 [(E)-3-[2-(4'-pyridyl)-vinyl]-1H-indole], an inhibitor of hepatic tryptophan dioxygenase, on brain quinolinic acid in mice.
Studies were undertaken to assess the role of the liver in the formation of the neurotoxin quinolinic acid in the brain. A selective and potent inhibitor of hepatic tryptophan 2,3-dioxygenase, 540C91 [(E)-3-[2-(4'-pyridyl)-vinyl]-1H-indole], largely prevented the elevation in mouse brain quinolinic acid resulting from parenteral injection of tryptophan (TRP). In contrast, 540C91 did not affect basal levels of the neurotoxin. Following induction of indoleamine dioxygenase with bacterial lipopolysaccharide, 540C91 was less effective in preventing the TRP-induced elevations in quinolinic acid. The data suggest that kynurenines, formed from tryptophan, by the liver and other extrahepatic organs can give rise to brain quinolinic acid.
Reinhard
J F
JF
Wellcome Research Laboratories, Research Triangle Park 27709, USA.
Flanagan
E M
EM
Madge
D J
DJ
Iyer
R
R
Salter
M
M
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007737:Kynurenine / Q000032:analysis; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017378:Quinolinic Acid / Q000378:metabolism*; D014364:Tryptophan / Q000097:blood / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
C097360:540C91; D004791:Enzyme Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid