Thiol-Based Redox Molecules: Potential Antidotes for Acrylamide Toxicity

Valeria Martin, Michael Trus, Daphne Atlas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

ACR induces activation of the MAPKs: ERK1/2, p38MAPK and JNK. Thioredoxin mimetic (TXM) peptides effectively inhibit ACR-induced activation of MAPKs. Inhibitory potency TXM-CB16/TXM-CB13 > AD4/NACA >NAC. TXM peptides reverse MAPK signaling and are promising ACR antidotes Highlights: Acrylamide (ACR) is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38MAPK), and c-Jun-N-terminal-kinases (JNKs). We established a reproducible assay testing N-acetylcysteine (NAC), AD4/NACA, and the N-and C-blocked tri- and tetra-thioredoxin-mimetic (TXM) peptides, in PC12 cells. Our results demonstrate that these compounds exhibited high efficacy in suppressing ACR-induced MAPK activation, either prior to or subsequent to ACR exposure. The inhibition by single cysteine (Cys) residue, NAC and AD4/NACA (NAC-amide), 2 Cys peptides TXM-CB30, AcDCys-Gly-DCysNH2, TXM-CB20, AcCys-Gly-CysNH2, SuperDopa (SD, Ac-CysL-Levodopa-CysNH2, TXM-CB13, AcCys-Met-Lys-CysNH2, and a 3-Cys peptide, TXM-CB16, AcCys-γGlu-Cys-CysNH2 was dose-dependent and potency displayed a direct correlation with the number of Cys residues. Cellular proteolysis of SD, which consists of levodopa flanked by two Cys, may suppress the manifestation of Parkinson’s disease (PD)-like symptoms mediated by chronic ACR exposure not only through lowering oxidative stress but also by replenishing cellular levels of dopamine. Overall, these results could advance the clinical application of TXM peptides as potential treatments for acute and/or chronic exposure to ACR and show promise as antidotes for preventing ACR-triggered PD-like neurotoxic symptoms.

Original languageEnglish
Article number1431
JournalAntioxidants
Volume13
Issue number12
DOIs
StatePublished - Dec 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • AD4/NACA
  • apoptosis
  • oxidative stress
  • thioredoxin reductase
  • toxicity

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