Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.
Several studies suggest that an increase of glutathione (GSH) through activation of the transcriptional nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the dopaminergic neurons may be a promising neuroprotective strategy in Parkinson's disease (PD). Among Nrf2 activators, isothiocyanate sulforaphane (SFN), derived from precursor glucosinolate present in Brassica vegetables, has gained attention as a potential neuroprotective compound. Bioavailability studies also suggest the contribution of SFN metabolites, including erucin (ERN), to the neuroprotective effects of SFN. Therefore, we compared the in vitro neuroprotective effects of SFN and ERN at the same dose level (5 μM) and oxidative treatment with 6-hydroxydopamine (6-OHDA) in SH-SY5Y cells. The pretreatment of SH-SY5Y cells with SFN recorded a higher (p < 0.05) active nuclear Nrf2 protein (12.0 ± 0.4 vs 8.0 ± 0.2 fold increase), mRNA Nrf2 (2.0 ± 0.3 vs 1.4 ± 0.1 fold increase), total GSH (384.0 ± 9.0 vs 256.0 ± 8.0 μM) levels, and resistance to neuronal apoptosis elicited by 6-OHDA compared to ERN. By contrast, the simultaneous treatment of SH-SY5Y cells with either SFN or ERN and 6-OHDA recorded similar neuroprotective effects with both the isothiocyanates (Nrf2 protein 2.2 ± 0.2 vs 2.1 ± 0.1 and mRNA Nrf2 2.1 ± 0.3 vs 1.9 ± 0.2 fold increase; total GSH 384.0 ± 4.8 vs 352.0 ± 6.4 μM). Finally, in vitro finding was confirmed in a 6-OHDA-PD mouse model. The metabolic oxidation of ERN to SFN could account for their similar neuroprotective effects in vivo, raising the possibility of using vegetables containing a precursor of ERN for systemic antioxidant benefits in a similar manner to SFN.
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