The neuroprotective activities of natural products through the Nrf2 upregulation

Abstract

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a basic‐region leucine zipper transcription factor that regulates the expression of many Phase II detoxifying/antioxidant enzymes. Many natural products act on the Nrf2 pathway and exhibit their preventive and/or therapeutic effects by activating Nrf2 and subsequently antioxidant enzymes. In this article, we reviewed the research literature that described Nrf2 activation as a mechanism for the neuroprotective effect of natural products. Our results showed that the inhibition of Kelch‐like ECH‐associated protein 1 and the activation of different intracellular kinases that lead to Nrf2 phosphorylation were the main mechanisms of Nrf2 upregulation suggested for these the natural products. Although some natural compounds such as terpenoids and alkaloids were reported to protect the nervous system by Nrf2 activating, flavonoids and phenolic compounds represent the majority of the reported neuroprotective natural substances that activate Nrf2. We also evaluated the physiochemical properties of some of the same substances to predict their oral bioavailability and central nervous system penetration. The results showed that sulforaphane and berberine have good oral bioavailability and would be predicted to cross through blood–brain barrier (BBB) easily, whereas the flavonoids in general would be predicted to be less effective in BBB transition because of their relatively high polar surface area.

Modulated Expression of the Protein Kinase GSK3 in Motor and Dopaminergic Neurons Increases Female Lifespan in Drosophila melanogaster

“…To search for the possible molecular mechanisms of the increase in lifespan due to the dominant-negative effect of sgg-RB A81T overexpression in dopaminergic neurons, we drew attention to nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates responses to multiple stressors. In particular, NRF2 mediates neuronal damage by modulating the expression of antioxidant enzymes (Tavakkoli et al, 2019). The activation of NRF2 due to suppression of the NRF2 repressor Keap1 extended the lifespan of D. melanogaster (Sykiotis and Bohmann, 2008;Spiers et al, 2019), and both Keap1 suppression and the constitutive overexpression of NRF2 positively modified neuronal function (Spiers et al, 2019).…”

Bioactive Molecules from Indian Medicinal Plants as Possible Candidates for the Management of Neurodegenerative Disorders

“…Berberine (33) has been shown to be neuroprotective through the Nrf2 upregulation and also alleviates rotenone-induced cytotoxicity by antioxidation and activation of PI3K/Akt signaling pathway in SH-SY5Y cells [82]. Neuroprotective effects of berberine have also been confirmed in animal models of Alzheimer's disease [83].…”

Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?

“…Different nutrients present in the human diet and plant-derived compounds show health promoting effects that are exerted, at least in part, by Nrf2 pathway. Among these ones, we can find isothiocyanates found in cruciferous vegetables, organosulfur compounds, polyphenols, and isoflavones that have been found to be Nrf2 activators [ 21 , 22 ].…”