title: Neostriatal and cortical quinolinate levels are increased in early grade Huntington's disease.
abstract: Huntington's disease (HD), an inherited neurodegenerative disorder, is caused by an abnormal polyglutamine expansion in the huntingtin protein. This genetic defect may result in heightened neuronal susceptibility to excitotoxic injury, a mechanism that has been postulated to play a critical role in HD. Quinolinate (QUIN) and kynurenate (KYNA), two endogenous neuroactive metabolites of the kynurenine pathway of tryptophan degradation, have been proposed to modulate excitotoxic neuronal death in HD. A third kynurenine pathway metabolite, the free radical generator 3-hydroxykynurenine (3-HK), has also been hypothesized to play a causal role in the pathogenesis of HD. We show here that the brain levels of both 3-HK and QUIN are increased three to four-fold in low-grade (grade 0/1) HD brain. These changes were seen in the neocortex and in the neostriatum, but not in the cerebellum. In contrast, brain 3-HK and QUIN levels were either unchanged or tended to decrease in grade 2 and advanced grade (grades 3-4) HD brain. Brain kynurenine and KYNA levels fluctuated only modestly as the illness progressed. These results support a possible involvement of 3-HK and QUIN in the early phases of HD pathophysiology and indicate novel therapeutic strategies against the disease.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guidetti
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Luthi-Carter
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Augood
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D007736:Kynurenic Acid / Q000378:metabolism; D008875:Middle Aged; D017072:Neostriatum / Q000378:metabolism*; D017378:Quinolinic Acid / Q000378:metabolism*
chemical_list: D017378:Quinolinic Acid; D007736:Kynurenic Acid