Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs

Abstract

Living cells maintain a balance between oxidation and reduction, and perturbations of this redox balance are thought to contribute to various diseases. Recent attempts to regulate redox state have focused on electrophiles (EPs), which activate potent cellular defense systems against oxidative stress. One example of this approach is exemplified by carnosic acid (CA) and carnosol (CS), compounds that are found in the herb rosemary (Rosmarinus officinalis). Importantly, CA and CS themselves are not electrophilic, but in response to oxidation, become electrophilic, and then activate the Keap1/Nrf2/ARE (antioxidant response element) transcription pathway to synthesize endogenous anti-oxidant ‘phase 2’ enzymes. As a result of our efforts to develop these compounds as therapeutics for brain health, we have formulated two innovative criteria for drug development: the first concept is the use of Pro-Electrophilic Drugs (PEDs) that are innocuous in and of themselves; and the second concept involves the use of compounds that are Pathologically-Activated Therapeutics (PATs), i.e., these small molecules are chemically converted to their active form by the very oxidative stress that they are designed to then combat. The chemical basis for PED and PAT drugs is embodied in the ortho- and para-hydroquinone electrophilic cores of the molecules, which are oxidized by the Cu2+/Cu+ cycling system (or potentially by other transition metals). Importantly, this cycling pathway is under stringent regulation by the cell redox state. We propose that redox-dependent quinone-formation is the predominant mechanism for formation of PED and PAT drugs from their precursor compounds. In fact, redox-dependent generation of the active form of drug from the “pro-form” distinguishes this therapeutic approach from traditional EPs such as curcumin, and results in a decrease in clinical side effects at therapeutic concentrations, e.g., lack of reaction with other thiols such as glutathione (GSH), which can result in lowering GSH and inducing oxidative stress in normal cells. We consider this pro-drug quality of PED/PAT compounds to be a key factor for generating drugs to be used to combat neurodegenerative diseases that will be clinically tolerated. Given the contribution of oxidative stress to the pathology of multiple neurodegenerative diseases, the Keap1/Nrf2/ARE pathway represents a promising drug target for these PED/PAT agents.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Numerous preclinical studies have reported that activation of NRF2 by natural compounds (Satoh et al, 2013) or by disrupting its negative regulator KEAP1 leads to potent anti-inflammatory effects in myeloid leukocytes and macrophages (Lin et al, 2008). In observational studies, a polymorphism in NFE2L2 was associated with reduced transcriptional activity correlating with increased risk of inflammatory bowel disease (Arisawa et al, 2008b) and chronic gastritis (Arisawa et al, 2007).…”

“…The majority of known physiologic or pharmacological NRF2 inducers are electrophilic molecules that covalently modify, by oxidation or alkylation, cysteine residues present in the thiol-rich KEAP1 protein (Hur and Gray, 2011;Satoh et al, 2013). KEAP1 is one of the best-suited proteins to act as electrophilic or redox sensor, as it contains 27 cysteine residues in humans and functions as an electrophile trap.…”

Protection or cytotoxicity mediated by a novel quinonoid-polyphenol compound?

“…On the other hand, quercetin and quinone rather enhanced the damage to cells. Polyphenol-mediated transition metal redox cycling (enhanced under H 2 O 2 -challenge) or the previously reported interaction with cultured media components might explain this outcome (Lapidot et al 2002;Satoh et al 2013). …”

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

“…We showed that CA up-regulates endogenous antioxidant phase II enzymes via the NRF2 transcriptional pathway. Moreover, this pathway is largely responsible for the mechanism of CA action because silencing Nrf2 significantly abrogated the protective effect (30,(40)(41)(42)(43). Here, we wanted to determine if CA could provide neuroprotection in the Mef2d +/− mice model of LIRD (44).…”