Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid.
Recent evidence suggests that there may be overactivation of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors in Huntington's disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16-sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p less than 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.
Beal
M F
MF
Department of Neurology, Massachusetts General Hospital, Boston 02114.
Matson
W R
WR
Swartz
K J
KJ
Gamache
P H
PH
Bird
E D
ED
D000368:Aged; D001344:Autopsy; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011699:Putamen / Q000032:analysis; D012016:Reference Values; D014364:Tryptophan / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D007737:Kynurenine; D014443:Tyrosine; D014364:Tryptophan; D007736:Kynurenic Acid