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Tanshinone I Induces Mitochondrial Protection through an Nrf2-Dependent Mechanism in Paraquat-TreatedHuman Neuroblastoma SH-SY5Y Cells

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Abstract

Tanshinone I (T-I; 1,6-Dimethylnaphtho[1,2-g][1]benzofuran-10,11-dione; C18H12O3), which may be found in Salvia miltiorrhiza Bunge (Danshen), is a potent anti-inflammatory, antioxidant, and anti-cancer agent. At least in part, T-I exerts antioxidant activity by activating signaling pathways associated with the maintenance of the redox state in mammalian cells. In this context, the upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has received attention regarding the role of this transcription factor in modulating the expression of antioxidant enzymes and the metabolism of glutathione (GSH). Even though there is a growing body of evidence suggesting that T-I mediates protection against several pro-oxidant challenges in both in vitro and in vivo experimental models, it remains to be examined whether and how T-I would modulate mitochondrial function during redox disturbances. Therefore, we aimed to reveal whether T-I would exhibit protective effects on mitochondria of SH-SY5Y cells treated with paraquat (PQ), a well-known mitochondrial toxic agent. We found that T-I pretreatment significantly protected mitochondria against PQ-induced redox impairment through an Nrf2-dependent mechanism involving upregulation of antioxidant enzymes, such as Mn-superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and both catalytic and modifier subunits of γ-glutamate-cysteine ligase (γ-GCL). T-I prevented complex I and mitochondrial membrane potential (MMP) impairments elicited by PQ. Thus, T-I may be viewed as a new mitochondrial protective agent whose complete mechanism of action needs to be investigated, but it seems to involve mitochondriotropic aspects related to the chemistry of this molecule.

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Acknowledgments

This work was partially supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). PFS is recipient of a CNPq fellow (Bolsista de Produtividade em Pesquisa 2—CA BF).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Química, Departamento de Química (DQ), Instituto de Ciências Exatas e da Terra (ICET), Universidade Federal de Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, 2367, CEP, Cuiabá, MT, 78060-900, Brazil

    Marcos Roberto de Oliveira

  2. Laboratório de Erros Inatos do Metabolismo, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Programa de Pós-Graduação em Ciências da Saúde, Criciúma, SC, Brazil

    Patrícia Fernanda Schuck

  3. Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil

    Simone Morelo Dal Bosco

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  1. Marcos Roberto de Oliveira
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Figure S1

The effects of paraquat (PQ) at different concentrations for 24 h on cell viability (A), cytotoxicity (B), and ROS production (C). (D) Cell viability of SH-SY5Y cells exposed to PQ at 100 μM for different periods. Data are presented as the mean ± SEM of three or five independent experiments each done in triplicate. One-way ANOVA followed by the post hoc Tukey’s test, *p < 0.05 vs the control group. (PDF 107 kb)

Figure S2

The effects of a pretreatment with tanshinone-I (T-I) at 1–5 μM for 2 h on cell viability (A), cytotoxicity (B), and ROS production (C). Data are presented as the mean ± SEM of three or five independent experiments each done in triplicate. One-way ANOVA followed by the post hoc Tukey’s test, *p < 0.05 vs the control group, # p < 0.05 different from PQ-treated group, a p < 0.01 different from PQ-treated cells. (PDF 105 kb)

Figure S3

The effects of a pretreatment with T-I at 2.5 μM for 2 h on (A) Bax immunocontent, (B) Bcl-2 immunocontent, (C) cytosolic cytochrome c content, (D) caspase-9 activity, (E) caspase-3 activity, and (F) DNA fragmentation. PQ was utilized at 100 μM for 24 h. Data are presented as the mean ± SEM of three or five independent experiments each done in triplicate. One-way ANOVA followed by the post hoc Tukey’s test, * p < 0.05 vs control cells, a p < 0.05 vs the cells treated with either PQ or T-I alone. (PDF 111 kb)

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de Oliveira, M.R., Schuck, P.F. & Bosco, S.M.D. Tanshinone I Induces Mitochondrial Protection through an Nrf2-Dependent Mechanism in Paraquat-TreatedHuman Neuroblastoma SH-SY5Y Cells. Mol Neurobiol 54, 4597–4608 (2017). https://doi.org/10.1007/s12035-016-0009-x

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