Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex.
Huntington's disease (HD) is characterized by gradually evolving selective neuronal death. Several lines of evidence suggest that an excitotoxic mechanism may play a role. Tryptophan metabolism leads to production of quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist, and to kynurenic acid, an antagonist at these same receptors. We recently found increased kynurenine to kynurenic acid ratios in HD postmortem putamen and decreased kynurenic acid concentrations in cerebrospinal fluid, consistent with decreased formation of kynurenic acid in HD brain. In the present study we used HPLC with 16 sensor coulometric electrochemical detection to measure kynurenic acid and 18 other electrochemically active compounds in 6 cortical regions, caudate and cerebellum from controls, HD, Alzheimer's disease (AD), and Parkinson's disease (PD) patients. Significant reductions in kynurenic acid concentrations were found in 5 of 6 cortical regions examined. Smaller reductions of kynurenic acid in the caudate, cerebellum and frontal pole were not significant. No significant reductions were found in the AD and PD patients. Both uric acid and glutathionine were significantly reduced in several regions of HD cerebral cortex, which could signify abnormal energy metabolism in HD. Since kynurenic acid is an antagonist of excitatory amino acid receptors, a deficiency could contribute to the pathogenesis of neuronal degeneration in HD.
Beal
M F
MF
Department of Neurology, Massachusetts General Hospital, Boston 02114.
Matson
W R
WR
Storey
E
E
Milbury
P
P
Ryan
E A
EA
Ogawa
T
T
Bird
E D
ED
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry*; D004734:Energy Metabolism; D005609:Free Radicals; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007736:Kynurenic Acid / Q000032:analysis*; D007737:Kynurenine / Q000378:metabolism; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D005609:Free Radicals; D011687:Purines; D007737:Kynurenine; D014443:Tyrosine; D014364:Tryptophan; D007736:Kynurenic Acid