Combating oxidative/nitrosative stress with electrophilic counterattack strategies

Abstract

Redox stress is thought to contribute to neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Cysteine-based redox regulation, via glutathione- and thioredoxin-mediated pathways, represents an acute defense system. Additionally, with prolonged oxidative stress, cells mount a 'counterattack' to activate transcription-dependent pathways, including the Keap1/Nrf2 and HSP90/HSF-1 pathways, which induce phase 2 enzymes and heat-shock proteins, respectively. Oxidative/nitrosative stress itself is an activator of the Keap1/Nrf2 pathway via cysteine thiol oxidation. Moreover, stress-induced oxidation of endogenous compounds can generate electrophiles, including active aldehydes, nitroso-compounds, fatty acids, nitro-guanosine, and quinone-based dopamine derivatives. These electrophilic compounds were considered toxic, but recently have been shown to be neuroprotective under certain conditions. These endogenously-produced electrophiles signal an electrophilic counterattack, binding to specific cysteines of Keap1 and HSP90 to activate these pathways. Finally, we describe novel pro-electrophilic drugs (PEDs) that are activated by the very oxidative/nitrosative stress that they subsequently counteract. One example is carnosic acid (CA), found in the herb rosemary. CA itself is not electrophilic, but in response to oxidation becomes electrophilic, and then activates the Keap1/Nrf2 pathway. PEDs appear to have minimal side effects, in part because they are generated preferentially in cells experiencing oxidative stress. In contrast, in the absence of oxidative stress, true electrophiles, unlike PEDs, react with and thus deplete glutathione, paradoxically rendering these normal cells susceptible to damage.