CommentaryThe Nrf2 pathway as a potential therapeutic target for Huntington disease: A commentary on “Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease”
Section snippets
HD pathogenesis and oxidative stress
HD is an inherited neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits, and psychiatric disturbances [2]. The disease is caused by an abnormal expansion of a CAG repeat in exon 1 of the gene encoding the huntingtin protein (Htt) [3]. This mutation confers a toxic function to Htt and leads to a partial loss of its trophic function. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the
Manipulation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) pathway to combat degeneration
One major system that orchestrates cell antioxidant defenses involves the transcription factor Nrf2. Under basal conditions, Nrf2 is maintained in the cytoplasm through its interaction with Keap1. Upon oxidative stress stimuli, Nrf2 dissociates from Keap1 and translocates to the nucleus, where it binds to the ARE DNA sequence and activates transcription of several target antioxidant genes, including glutathione (GSH)-synthesizing enzymes, heme oxygenase (HO-1), and NAD(P)H quinone
What are the mechanisms underlying the effects of CDDO-EA and CDDO-TFEA in HD mice?
Further studies will be needed to fully understand the underlying mechanisms of neuroprotection described by Stack and collaborators. First, it is important to demonstrate that the effects of CDDO-EA and CDDO-TFEA are, at least in part, mediated by Nrf2 induction in the brain. The level of HO-1 mRNA, a known target gene of Nrf2, was modestly increased in the brain of transgenic mice fed CDDO-EA and CDDO-TFEA. However, GST3a and NQO1, two other genes controlled by Nrf2 and whose upregulation
Conclusion
There is now cumulative preclinical data arguing that the Nrf2/ARE pathway is a potent therapeutic pathway for HD [1], [8], [13], [15], [16]. With such potent and pleiotropic effects, the Nrf2/ARE pathway seems to be a very promising candidate even for other brain diseases associated with oxidative stress and inflammation. The paper by Stack and collaborators further supports this view. However, future preclinical developments on CDDO-EA and CDDO-TFEA require a better understanding of their
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