title: Inhibition of Early Biochemical Defects in Prodromal Huntington's Disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients.
abstract: Huntington's disease (HD) is a progressive fatal dominant hereditary neurodegenerative disease of the brain, which primarily affects the cortex and the striatum. The disorder is typified by an expansion of more than 35 repeats of the nucleotide triplet cytosine- adenine-guanosine (CAG) which codes for the amino acid glutamine in the huntingtin gene. Despite studies of several decades, there are no effective means to block or postpone the appearance of symptoms of HD. Analysis of these studies led us to propose that increased oxidative stress and chronic inflammation are earliest events in the pathogenesis of HD, and together with excessive glutamate release, participate in the progression of the disease. This review briefly describes evidence for the involvement of oxidative stress, chronic inflammation and glutamate in the pathogenesis of HD. It is proposed that attenuation of these biochemical abnormalities together, may delay the appearance of symptoms of HD. In order to achieve this goal, the simultaneous activation of the nuclear transcriptional factor-2/antioxidant response elements (Nrf2/ARE) pathway that would enhance the transcription of target genes coding for antioxidant enzymes and phase-2-detoxifying enzymes, and an elevation of the levels of antioxidant compounds by supplementation may be needed. Normal mechanisms of activation of Nrf2 requiring reactive oxygen species (ROS) may be impaired in HD, but certain antioxidant compounds can activate Nrf2 without ROS. Use of a combination of micronutrients that can activate the Nrf2/ARE pathway and enhance the levels of antioxidant compounds is suggested.
authors.forename: Kedar N
authors.initials: KN
authors.lastname: Prasad
authors.affiliation: Center for Occupational and Environmental Health Department of Medicine University of California, Irvine, CA 92697-1830, USA. scbondy@uci.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bondy
mesh_terms: D000818:Animals; D001669:Biochemical Phenomena; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species