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Oxidative Stress and Redox Regulation pp 277–307Cite as

Combating Oxidative/Nitrosative Stress with Electrophilic Counterattack Strategies

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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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Authors and Affiliations

  1. Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA

    Takumi Satoh, Mohd Waseem Akhtar & Stuart A. Lipton

  2. Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate, 020-8551, Japan

    Takumi Satoh

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  1. Takumi Satoh
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  2. Mohd Waseem Akhtar
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  3. Stuart A. Lipton
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Correspondence to Takumi Satoh or Stuart A. Lipton .

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  1. Mol.,Cel. and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA

    Ursula Jakob

  2. The Alexander Silberman Institute of Life Science, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

    Dana Reichmann

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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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