Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice.
The brain levels of the endogenous excitotoxin quinolinic acid (QUIN) and its bioprecursor, the free radical generator 3-hydroxykynurenine (3-HK), are elevated in early stage Huntington disease (HD). We now examined the status of these metabolites in three mouse models of HD. In R6/2 mice, 3-HK levels were significantly and selectively elevated in the striatum, cortex and cerebellum starting at 4 weeks of age. In contrast, both 3-HK and QUIN levels were increased in the striatum and cortex of the full-length HD models, beginning at 8 months (YAC128) and 15 months (Hdh(Q92) and Hdh(Q111)), respectively. No changes were seen in 13-month-old shortstop mice, which show no signs of motor or cognitive dysfunction or selective neuropathology. These results demonstrate both important parallels and intriguing differences in the progressive neurochemical changes in these HD mouse models and support the hypothesis that QUIN may play a role in the striatal and cortical neurodegeneration of HD.
Guidetti
Paolo
P
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Bates
Gillian P
GP
Graham
Rona K
RK
Hayden
Michael R
MR
Leavitt
Blair R
BR
MacDonald
Marcy E
ME
Slow
Elizabeth J
EJ
Wheeler
Vanessa C
VC
Woodman
Ben
B
Schwarcz
Robert
R
D000367:Age Factors; D000818:Animals; D001923:Brain Chemistry; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017378:Quinolinic Acid / Q000032:analysis* / Q000378:metabolism
C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid