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

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.

Neuronal activity regulates astrocytic Nrf2 signaling

“…3). These findings are consistent with the previous work, which showed (i) that, based on gene-expression profiling, activation of synaptic NMDAR in neuronal cultures does not lead to induction of classic Nrf2-regulated genes (12); and (ii) that activity-dependent induction of sulfiredoxin in neuronal cultures is largely independent of Nrf2, although this gene can be upregulated in neurons by treatment with pharmacologic Nrf2 inducers (19). Astrocytic Nrf2 signaling was up-regulated in response to elevated neuronal activity in intact brain slices (Fig.…”

Dithiol-based Compounds Maintain Expression of Antioxidant Protein Peroxiredoxin 1 That Counteracts Toxicity of Mutant Huntingtin

“…Once in the nucleus, Nrf2 dimerizes with a small Maf protein and the heterodimer then binds antioxidant response element sequences within the promoters of antioxidant and phase II detoxifying genes. Besides activating transcription of Prx1, Nrf2 can also activate expression of sulfiredoxin, an enzyme that can reverse oxidation of Prx sulfinic acids to sulfhydryl groups and various other antioxidant enzymes (37). The observation that DMP exposure can partially rescue mHtt-induced toxicity even when Prx1 expression is knocked down (Fig.…”

Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

“…1E). Proportional to the expression level of caNrf2, up-regulation of the established Nrf2 target genes Nqo1, Gsta3 (glutathione S-transferase 3), Gclc (glutamate cysteine ligase, catalytic subunit), and Srxn1 (sulfiredoxin1) (Kensler et al 2007;Soriano et al 2008) was detected by RPA or quantitative RT-PCR (qRT-PCR) (Fig. 1F,G).…”