Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione

Francesc X. Soriano, Frederic Leveille, Sofia Papadia, Larry G. Higgins, James Varley, Paul Baxter, John D. Hayes, Giles E. Hardingham

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    92 Citations (Scopus)

    Abstract

    Peroxiredoxins are an important family of cysteine-based antioxidant enzymes that exert a neuroprotective effect in several models of neurodegeneration. However, under oxidative stress they are vulnerable to inactivation through hyperoxidation of their active site cysteine residues. We show that in cortical neurons, the chemopreventive inducer 3H-1,2-dithiole-3-thione (D3T), that activates the transcription factor Nuclear factor erythroid 2-related factor (Nrf2), inhibits the formation of inactivated, hyperoxidized peroxiredoxins following oxidative trauma, and protects neurons against oxidative stress. In both neurons and glia, Nrf2 expression and treatment with chemopreventive Nrf2 activators, including D3T and sulforaphane, up-regulates sulfiredoxin, an enzyme responsible for reducing hyperoxidized peroxiredoxins. Induction of sulfiredoxin expression is mediated by Nrf2, acting via a cis- acting antioxidant response element (ARE) in its promoter. The ARE element in Srxn1 contains an embedded activator protein-1 (AP-1) site which directs induction of Srxn1 by synaptic activity. Thus, raising Nrf2 activity in neurons prevents peroxiredoxin hyperoxidation and induces a new member of the ARE-gene family, whose enzymatic function of reducing hyperoxidized peroxiredoxins may contribute to the neuroprotective effects of Nrf2 activators.

    Original languageEnglish
    Pages (from-to)533-543
    Number of pages11
    JournalJournal of Neurochemistry
    Volume107
    Issue number2
    DOIs
    Publication statusPublished - Oct 2008

    Keywords

    • chemoprevention
    • neurodegeneration
    • neuroprotection
    • oxidative stress
    • phase II enzymes
    • thioredoxin
    • ANTIOXIDANT RESPONSE ELEMENT
    • OXIDATIVE STRESS
    • GENE-EXPRESSION
    • NOTCH-RESPONSIVENESS
    • PARKINSONS-DISEASE
    • CEREBRAL-ISCHEMIA
    • SIGNALING PATHWAY
    • SULFINIC ACID
    • NUCLEAR CA2+
    • CELL-DEATH

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