Kynurenine pathway enzymes in brain: responses to ischemic brain injury versus systemic immune activation.
Accumulation of L-kynurenine and quinolinic acid (QUIN) in the brain occurs after either ischemic brain injury or after systemic administration of pokeweed mitogen. Although conversion of L-[13C6]tryptophan to [13C6]-QUIN has not been demonstrated in brain either from normal gerbils or from gerbils given pokeweed mitogen, direct conversion in brain tissue does occur 4 days after transient cerebral ischemia. Increased activities of enzymes distal to indoleamine-2,3-dioxygenase may determine whether L-kynurenine is converted to QUIN. One day after 10 min of cerebral ischemia, the activities of kynureninase and 3-hydroxy-3,4-dioxygenase were increased in the hippocampus, but local QUIN levels and the activities of the indoleamine-2,3-dioxygenase and kynurenine-3-hydroxylase were unchanged. By days 2 and 4 after ischemia, however, the activities of all these enzymes in the hippocampus as well as QUIN levels were significantly increased. Kynurenine aminotransferase activity in the hippocampus was unchanged on days 1 and 2 after ischemia but was decreased on day 4, at a time when local kynurenic acid levels were unchanged. A putative precursor of QUIN, [13C6]anthranilic acid, was not converted to [13C6]QUIN in the hippocampus of either normal or 4-day post-ischemic gerbils. Gerbil macrophages stimulated by endotoxin in vitro converted L-[13C6]tryptophan to [13C6]QUIN. Kinetic analysis of kynurenine-3-hydroxylase activity in the cerebral cortex of postischemic gerbils showed that Vmax increased, without changes in Km. Systemic administration of pokeweed mitogen increased indoleamine-2,3-dioxygenase and kynureninase activities in the brain without significant changes in kynurenine-3-hydroxylase or 3-hydroxyanthranilate-3,4-dioxygenase activities. Increases in kynurenine-3-hydroxylase activity, in conjunction with induction of indoleamine-2,3-dioxygenase, kynureninase, and 3-hydroxyanthranilate-3,4-dioxygenase in macrophage infiltrates at the site of brain injury, may explain the ability of postischemic hippocampus to convert L-[13C6]tryptophan to [13C6]QUIN.
Saito
K
K
Section on Analytical Biochemistry, National Institute of Mental Health, Bethesda, Maryland 20892.
Nowak
T S
TS
Suyama
K
K
Quearry
B J
BJ
Saito
M
M
Crowley
J S
JS
Markey
S P
SP
Heyes
M P
MP
D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002247:Carbon Isotopes; D049308:Dioxygenases; D005260:Female; D005849:Gerbillinae; D006867:Hydrolases / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D007700:Kinetics; D007737:Kynurenine / Q000096:biosynthesis / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008190:Lyases; D008213:Lymphocyte Activation; D008928:Mitochondria / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009928:Organ Specificity; D010105:Oxygenases / Q000378:metabolism; D011043:Pokeweed Mitogens; D017378:Quinolinic Acid / Q000378:metabolism; D013574:Synaptosomes / Q000201:enzymology; D000637:Transaminases / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism
D002247:Carbon Isotopes; D011043:Pokeweed Mitogens; D007737:Kynurenine; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D049308:Dioxygenases; D014366:Tryptophan Oxygenase; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D006867:Hydrolases; C021480:kynureninase; D008190:Lyases; D017378:Quinolinic Acid