Edinburgh Research Explorer Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione
Citation for published version: Soriano, FX, Leveille, F, Papadia, S, Higgins, LG, Varley, J, Baxter, P, Hayes, JD & Hardingham, GE 2008, 'Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione', Journal of Neurochemistry, vol. 107, no. 2, pp. 533-543. https://doi.org/10.1111/j.1471-4159.2008.05648.x
Digital Object Identifier (DOI): 10.1111/j.1471-4159.2008.05648.x
Link: Link to publication record in Edinburgh Research Explorer
Document Version: Peer reviewed version
Published In: Journal of Neurochemistry
Publisher Rights Statement: Published in final edited form as: J Neurochem. 2008 October ; 107(2): 533–543. doi:10.1111/j.1471-4159.2008.05648.x.
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Download date: 30. Sep. 2021 JOURNAL OF NEUROCHEMISTRY | 2008 | 107 | 533–543 doi: 10.1111/j.1471-4159.2008.05648.x
*Centre for Neuroscience Research, University of Edinburgh, Edinburgh, UK Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
Abstract responsible for reducing hyperoxidized peroxiredoxins. Peroxiredoxins are an important family of cysteine-based Induction of sulfiredoxin expression is mediated by Nrf2, act- antioxidant enzymes that exert a neuroprotective effect in ing via a cis-acting antioxidant response element (ARE) in its several models of neurodegeneration. However, under oxi- promoter. The ARE element in Srxn1 contains an embedded dative stress they are vulnerable to inactivation through activator protein-1 (AP-1) site which directs induction of Srxn1 hyperoxidation of their active site cysteine residues. We show by synaptic activity. Thus, raising Nrf2 activity in neurons that in cortical neurons, the chemopreventive inducer 3H-1,2- prevents peroxiredoxin hyperoxidation and induces a new dithiole-3-thione (D3T), that activates the transcription factor member of the ARE-gene family, whose enzymatic function of Nuclear factor erythroid 2-related factor (Nrf2), inhibits the reducing hyperoxidized peroxiredoxins may contribute to the formation of inactivated, hyperoxidized peroxiredoxins fol- neuroprotective effects of Nrf2 activators. lowing oxidative trauma, and protects neurons against oxi- Keywords: chemoprevention, neurodegeneration, neuropro- dative stress. In both neurons and glia, Nrf2 expression and tection, oxidative stress, phase II enzymes, thioredoxin. treatment with chemopreventive Nrf2 activators, including J. Neurochem. (2008) 107, 533–543. D3T and sulforaphane, up-regulates sulfiredoxin, an enzyme
Oxidative stress occurs because of an imbalance between These Prxs contain a peroxidatic cysteine residue, oxidized production of reactive oxygen species and the cell’s capacity by peroxides to cysteine sulfenic acid, which then forms a to neutralize them through its intrinsic antioxidant defences. disulfide bond with the resolving cysteine, which is in turn Key among these is the thioredoxin-peroxiredoxin system reduced by thioredoxin (Wood et al. 2003). Sometimes, Prx- which is an important reducer of oxidative stressors such as sulfenic acid is further oxidized by peroxide to sulfinic peroxides (Winyard et al. 2005). The thioredoxin system (-SO2H) or sulfonic (-SO3H) acid, causing inactivation of protects against H2O2-induced apoptosis, and its inhibition peroxidase activity (Rhee et al. 2007). Prx-SO2/3H is not a promotes oxidative stress and cell death (Yoshida et al. substrate for the resolving cysteine and cannot be reduced by 2005). The thioredoxin-peroxiredoxin system detoxifies peroxides by transferring reducing equivalents from NADPH to peroxides via thioredoxin reductase, thioredoxin and Received July 23, 2008; revised manuscript received August 8, 2008; finally peroxiredoxins (Prxs). Prxs are a ubiquitous family of accepted August 12, 2008. Address correspondence and reprint requests to Giles E. Hardingham, peroxidases with cytoprotective and antioxidative effects Centre for Neuroscience Research, University of Edinburgh, Edinburgh (Immenschuh and Baumgart-Vogt 2005). The 2-Cys Prxs is EH8 9XD, UK. E-mail: [email protected] the predominant Prx subfamily, comprising Prx I-IV (Wood Abbreviations used: ARE, antioxidant response element; AP-1, acti- et al. 2003) and are implicated in protecting neuronal cells vator protein-1; D3T, 3H-1,2-dithiole-3-thione; GAPDH, Glycer- from Ab toxicity (Yao et al. 2007), excitotoxicity (Hattori aldehyde-3-phosphate dehydrogenase; GFAP, Glial fibrillary acidic protein; DAPI, 4,6-diamino-2-phenylindole; eGFP, enhanced green et al. 2003), oxygen-glucose deprivation (Boulos et al. fluorescent protein; NeuN, Neuronal nuclear antigen; Nrf2, Nuclear 2007), peroxide (Sanchez-Font et al. 2003; Fang et al. factor erythroid 2-related factor; Prx, Peroxiredoxin; tBHQ, tert- 2007), and MPP+ toxicity (Qu et al. 2007). butylhydroquinone.