Natural Products as Modulators of Nrf2 Signaling Pathway in Neuroprotection

Abstract

Neurodegenerative diseases (NDs) affect the West due to the increase in life expectancy. Nervous cells accumulate oxidative damage, which is one of the factors that triggers and accelerates neurodegeneration. However, cells have mechanisms that scavenge reactive oxygen species (ROS) and alleviate oxidative stress (OS). Many of these endogenous antioxidant systems are regulated at the gene expression level by the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). In the presence of prooxidant conditions, Nrf2 translocates to the nucleus and induces the transcription of genes containing ARE (antioxidant response element). In recent years, there has been an increase in the study of the Nrf2 pathway and the natural products that positively regulate it to reduce oxidative damage to the nervous system, both in in vitro models with neurons and microglia subjected to stress factors and in vivo models using mainly murine models. Quercetin, curcumin, anthocyanins, tea polyphenols, and other less studied phenolic compounds such as kaempferol, hesperetin, and icariin can also modulate Nrf2 by regulating several Nrf2 upstream activators. Another group of phytochemical compounds that upregulate this pathway are terpenoids, including monoterpenes (aucubin, catapol), diterpenes (ginkgolides), triterpenes (ginsenosides), and carotenoids (astaxanthin, lycopene). This review aims to update the knowledge on the influence of secondary metabolites of health interest on the activation of the Nrf2 pathway and their potential as treatments for NDs.

Protective effects of polyphenol-rich extracts against neurotoxicity elicited by paraquat or rotenone in cellular models of Parkinson’s disease

“…Thus, an increase in Nrf2 transcriptional activity is detected as an increase in cellular EGFP fluorescence in the transduced cells. Transduced cortical astrocytes treated with curcumin (10 μM), a known Nrf2 activator that serves as a positive control in the reporter assay 25,26,29,46 , showed a 5 to 8-fold increase in EGFP fluorescence intensity compared to control cells (data not shown). Cortical astrocytes treated with extract prepared from BB, wild BB, or GSk, or with the individual ANC C3G, D3G, or M3G, showed a ~1.3 to 2.0-fold increase in EGFP fluorescence relative to control levels (Figure 5).…”

“…Nrf2 is a redox-responsive transcription factor responsible for regulating the expression of cellular antioxidant proteins 44 . Multiple lines of evidence suggest that polyphenols modulate Nrf2 transcriptional activity 25,26,29,45,46 . Because PQ and rotenone are both thought to elicit neurotoxicity by eliciting oxidative stress, we hypothesized that at least a subset of botanical extracts might protect dopaminergic neurons against PD-related toxins by activating the Nrf2mediated antioxidant response.…”

Molecular interplay between phytoconstituents of Ficus Racemosa and neurodegenerative diseases

“…These cellular mechanisms collectively highlight terpenoids' potential as neuroprotective agents, offering avenues for therapeutic interventions in neurodegenerative disorders characterized by Aβ‐induced inflammation and oxidative stress. Terpenoids have been demonstrated to elicit the activation of the Nrf2 signalling pathway, leading to augmented synthesis of crucial antioxidant enzymes, notably HO‐1, NQO1, SOD, and CAT (Moratilla‐Rivera et al, 2023). This orchestrated response ultimately serves to curtail ROS production and mitigate neuronal damage (Branca et al, 2020).…”

Microalgae as a Nutraceutical Tool to Antagonize the Impairment of Redox Status Induced by SNPs: Implications on Insulin Resistance

“…In particular, this phenolic compound can be produced by Tetraselmis suecica and Nannochloropsis gaditana [ 174 ]. It was reported that quercetin can directly scavenge free radicals due to the presence of two antioxidant pharmacophores in the molecule, induce the expression of NRF2, and also inhibit ROS-associated inflammation by blocking IKK-β and the nuclear translocation of NF-kB [ 175 , 176 , 177 ] ( Figure 2 ). Quercetin can be integrated into the diet to stimulate insulin secretion, to protect beta cells from ROS, and to ameliorate the antioxidant defence and inflammation, therefore improving IR [ 178 ].…”