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Review
. 2020 Oct 24;25(21):4926.
doi: 10.3390/molecules25214926.

Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review

Sajad Fakhri  1 , Mirko Pesce  2 , Antonia Patruno  2 , Seyed Zachariah Moradi  1   3 , Amin Iranpanah  4 , Mohammad Hosein Farzaei  1 , Eduardo Sobarzo-Sánchez  5   6
Affiliations
Review

Attenuation of Nrf2/Keap1/ARE in Alzheimer's Disease by Plant Secondary Metabolites: A Mechanistic Review

Sajad Fakhri et al. Molecules. .

Abstract

Alzheimer's disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

Keywords: Alzheimer’s disease; Keap1; Nrf2; antioxidant response elements; oxidative stress; pharmacology; phytochemicals; secondary metabolites.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General overview of Nrf2/Keap1/ARE and interconnected pathways, how to be targeted by phytochemicals. Phytochemicals activate Nrf2, ARE (e.g., SOD, CAT, GPx, GSH, GST) and autophagy, while inhibits Keap1, oxidative mediators (e.g., ROS, MDA, NO, iNOS) and inflammation (IL, TNF-α, NF-κB). ↑ green: Activate or up-regulation, ⊥ red: inhibit or down-regulation, ARE: antioxidant response element, CAT: catalase, GPCRs: G protein-coupled receptors, GPx: glutathione peroxidase, GSH: glutathione, GSK-3β: glycogen synthase kinase 3-beta, GST: glutathione S-transferase, IL: interleukin, iNOS: inducible nitric oxide synthase, Keap1: Kelch-like ECH-associated protein-1, MDA: malondialdehyde, mTORc: mammalian target of rapamycin, NF-κB: nuclear factor-κB, NO: nitric oxide, Nrf2: nuclear factor erythroid 2-related factor 2, ROS: reactive oxygen species, RTKs: receptor tyrosine kinase, SOD: superoxide dismutase, TNF-α: tumor necrosis factor-α.
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References

    1. Weuve J., Hebert L.E., Scherr P.A., Evans D.A. Deaths in the United States among persons with Alzheimer’s disease (2010–2050) Alzheimer’s Dement. 2014;10:e40–e46. doi: 10.1016/j.jalz.2014.01.004. - DOI - PMC - PubMed
    1. Gan L., Johnson J.A. Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2014;1842:1208–1218. doi: 10.1016/j.bbadis.2013.12.011. - DOI - PubMed
    1. Skibinski G., Hwang V., Ando D.M., Daub A., Lee A.K., Ravisankar A., Modan S., Finucane M.M., Shaby B.A., Finkbeiner S. Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis. Proc. Natl. Acad. Sci. USA. 2016;114:1165–1170. doi: 10.1073/pnas.1522872114. - DOI - PMC - PubMed
    1. Teixeira J.P., De Castro A.A., Soares F.V., Da Cunha E.F.F., Ramalho T.C. Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis. Molecules. 2019;24:4410. doi: 10.3390/molecules24234410. - DOI - PMC - PubMed
    1. McMahon M., Lamont D.J., Beattie K.A., Hayes J.D. Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc. Natl. Acad. Sci. USA. 2010;107:18838–18843. doi: 10.1073/pnas.1007387107. - DOI - PMC - PubMed

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