3-Hydroxykynurenine and quinolinate: pathogenic synergism in early grade Huntington's disease?

Huntington's Disease (HD), an inherited neurodegenerative disorder, is caused by an abnormal polyglutamine extension of a protein named huntingtin. This genetic defect is believed to result in heightened neuronal susceptibility to excitotoxic injury, a likely mechanism of neurodegeneration in HD. Two neuroactive kynurenine pathway metabolites, quinolinate (QUIN) and kynurenate (KYNA), have been proposed to play critical roles in the precipitation and prevention, respectively, of excitotoxic neuron death in HD. We now provide evidence that a third kynurenine pathway metabolite, 3-hydroxykynurenine (3-HK), should also be considered a pathogen in HD. The brain levels of this free radical generator are increased 5-10-fold in early stage (Grade 1) HD patients. In the same brains, QUIN levels are also significantly elevated in the cortex and in the neostriatum, but not in the cerebellum. In contrast, brain 3-HK and QUIN levels are either unchanged or reduced in Grade 2 and end stage (Grade 3-4) HD patients. Brain KYNA levels are moderately increased during the early disease stages and decrease as the illness progresses. In rats, 3-HK potentiates striatal QUIN toxicity, and this pro-excitotoxic effect can be prevented by free radical scavengers. Taken together, these studies provide further evidence for an involvement of kynurenine pathway metabolites in the early phases of HD neuropathology and suggest novel therapeutic strategies for the disease.