Title:Inhibition of Early Biochemical Defects in Prodromal Huntington’s disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients
VOLUME: 9 ISSUE: 1
Author(s):Kedar N. Prasad and Stephen C. Bondy
Affiliation:Center for Occupational and Environmental Health Department of Medicine University of California, Irvine, CA 92697-1830, USA.
Keywords:Antioxidants, glutamate release, Huntington’s disease, inflammation, micronutrients, nuclear transcriptional factor
Nrf2, oxidative stress.
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.
