Abstract
Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant whose mechanisms of action involve oxidation of endogenous nucleophilic groups (mainly thiols and selenols), depletion of antioxidant defenses, and disruption of neurotransmitter homeostasis. Diphenyl diselenide—(PhSe)2—a model diaryl diselenide, has been reported to display significant protective effects against MeHg-induced neurotoxicity under both in vitro and in vivo experimental conditions. In this study, we compared the protective effects of (PhSe)2 with those of RC513 (4,4′-diselanediylbis(2,6-di-tert-butylphenol), a novel diselenide-probucol-analog) against MeHg-induced toxicity in the neuronal (hippocampal) cell line HT22. Although both (PhSe)2 and RC513 significantly mitigated MeHg- and tert-butylhydroperoxide (t-BuOOH)-cytotoxicity, the probucol analog exhibited superior protective effects, which were observed earlier and at lower concentrations compared to (PhSe)2. RC513 treatment (at either 0.5 µM or 2 µM) significantly increased glutathione peroxidase (GPx) activity, which has been reported to counteract MeHg-toxicity. (PhSe)2 was also able to increase GPx activity, but only at 2 µM. Although both compounds increased the Gpx1 transcripts at 6 h after treatments, only RC513 was able to increase mRNA levels of Prx2, Prx3, Prx5, and Txn2, which are also involved in peroxide detoxification. RC513 (at 2 µM) significantly increased GPx-1 protein expression in HT22 cells, although (PhSe)2 displayed a minor (nonsignificant) effect in this parameter. In agreement, RC513 induced a faster and superior capability to cope with exogenously-added peroxide (t-BuOOH). In summary, when compared to the prototypical organic diaryl diselenide [(PhSe)2], RC513 displayed superior protective properties against MeHg-toxicity in vitro; this was paralleled by a more pronounced upregulation of defenses related to detoxification of peroxides, which are well-known MeHg-derived intermediate oxidant species.
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Funding
The financial support by (i) Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), (ii) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and (iii) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) is gratefully acknowledged. MF, AFB, RBL, JBT, and ALB are CNPq fellowship recipients. Part of the work was performed with the support from LAMEB (Laboratório Multiusuário de Ciências Biológicas—UFSC), whose technicians are gratefully acknowledged. The authors are also thankful to CEBIME-UFSC for mass analyses. MA was partly supported by a grant from the National Institute of Environmental Health Sciences (NIEHS), R01ES07331.
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Quispe, R.L., Jaramillo, M.L., Wolin, I.A.V. et al. A Novel Diselenide-Probucol-Analogue Protects Against Methylmercury-Induced Toxicity in HT22 Cells by Upregulating Peroxide Detoxification Systems: a Comparison with Diphenyl Diselenide. Neurotox Res 40, 127–139 (2022). https://doi.org/10.1007/s12640-021-00466-3
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DOI: https://doi.org/10.1007/s12640-021-00466-3