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

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.

An Inhibitor of NF-κB and an Agonist of AMPK: Network Prediction and Multi-Omics Integration to Derive Signaling Pathways for Acteoside Against Alzheimer’s Disease

“…Alzheimer’s disease is a progressive neuronal and cognitional dysfunction disease with complex dysregulated mechanisms ( Fakhri et al, 2020 ). Accumulating evidence has demonstrated that there is a significant association between microglia-driven inflammation in the brain.…”

Acteoside Repressed Microglia M1 Polarization Through Inhibited NF-κB Signalling Pathway and AMPK-Mediated Mitochondria Function Recovery

“…AD is a progressive neuronal and cognitional dysfunction disease, with complex dysregulated mechanisms [17] . Accumulating evidence has demonstrated a signi cant association between microgliadriven in ammation in the brain.…”

Targeting Neurological Manifestations of Coronaviruses by Candidate Phytochemicals: A Mechanistic Approach

“…Based on molecular dynamic analysis Kumar et al indicated that some other phenolic compounds play important roles in the inhibition of SARS-CoV-2 such as rosmarinic acid, ferulic acid, ursonic acid, piperine, gingerol, curcumin, and silymarin ( Kumar et al, 2020 ). Previously the neuroprotective effects of such plant-derived secondary metabolites have been reported through inhibiting the inflammatory-interconnected mediators ( Abbaszadeh et al, 2020 ; Fakhri et al, 2020b ). Among the aforementioned phytochemicals, ferulic acid, silymarin and curcumin possess particular anti-neuroinflammatory effects, in addition to related antiviral effects ( Dutta et al, 2009 ; Borah et al, 2013 ; Ghosh et al, 2017 ).…”

“…Several other phytochemicals play important roles in the inhibition of SARS-CoV-2 such as sarsasapogenin (a steroidal sapogenin), novobiocin (a coumarin), and alpha terpinyl acetate (a terpenoid) ( Kumar et al, 2020 ). Previously the neuroprotective effects of such plant-derived secondary metabolites have been reported through inhibiting the inflammatory-interconnected mediators ( Abbaszadeh et al, 2020 ; Fakhri et al, 2020b ).…”