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.
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Abbreviations
- ABCC:
-
ATP-binding cassette, sub-family C
- AD:
-
Alzheimer’s disease
- ARE:
-
antioxidant response element
- BDNF:
-
brain-derived neurotrophic factor
- CA:
-
carnosic acid
- CAB:
-
biotinylated carnosic acid
- CNTF:
-
ciliary neurotrophic factor
- DA:
-
dopamine
- EP:
-
electrophile
- ER:
-
endoplasmic reticulum
- GCLM:
-
glutamyl cysteine ligase modifier subunit
- GCLC:
-
glutamyl cysteine ligase catalytic subunit
- GSSG:
-
disulfide form of glutathione
- GPX:
-
glutathione peroxidase
- GR:
-
NADPH-dependent GSSG reductase
- GST:
-
glutathione-S-transferase
- HHE:
-
trans-4-hydroxy-2-hexenal
- HNE:
-
trans-4-hydroxy-2-nonenal
- H2O2 :
-
hydrogen peroxide
- HO-1:
-
hemeoxygenase-1
- HSE:
-
heat-shock factor response element
- HSF-1:
-
heat-shock factor-1
- HSP:
-
heat-shock protein
- ∙HO:
-
hydroxyl radical
- NEPP:
-
neurite outgrowth-promoting prostaglandin
- NMDA:
-
N-methyl-d-aspartate
- NO2 :
-
nitric dioxide
- NO:
-
nitric oxide
- NQO1:
-
NADPH quinone oxidoreductase 1
- NGF:
-
nerve growth factor
- ∙O2 − :
-
superoxide radical anion
- ONOO− :
-
peroxynitrite
- PAT:
-
pathologically activated therapeutic
- PUFA:
-
poly-unsaturated fatty acids
- PRX:
-
peroxyredoxin
- PED:
-
pro-electrophilic drug
- RNS:
-
reactive nitrogen species
- ROS:
-
reactive oxygen species
- SRXN:
-
ATP-dependent reductase, sulfiredoxin
- TBHQ:
-
tert-butyl hydroquinone
- TRX:
-
thioredoxin
- TRXR:
-
thioredoxin reductase
- xCT:
-
Na+-independent cystine-glutamate exchanger
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Acknowledgments
We thank Drs. Larry D. Frye (Biomdcom) and Scott McKercher for help with manuscript preparation and Dr. Tomohiro Nakamura (Sanford-Burnham Medical Research Institute) for valuable discussions concerning chemical reactions. Our studies described in this chapter were supported in part by a grant from the JSPS, Joint Project of Japan–U.S., from the MEXT Japan, from Grants-in-Aid for Scientific Research (No.19500261; No. 22500282), and from Grants-in-Aid for Scientific Research on Innovative Areas (No. 2011701) to T.S. Other support for our studies came from NIH grants R01 EY05477, P01 ES016738, P01 HD29587, and P30 NS057096/P30 NS076411 to S.A.L.
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Satoh, T., Akhtar, M.W., Lipton, S.A. (2013). Combating Oxidative/Nitrosative Stress with Electrophilic Counterattack Strategies. In: Jakob, U., Reichmann, D. (eds) Oxidative Stress and Redox Regulation. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5787-5_10
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