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Pinocembrin Attenuates Mitochondrial Dysfunction in Human Neuroblastoma SH-SY5Y Cells Exposed to Methylglyoxal: Role for the Erk1/2–Nrf2 Signaling Pathway

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Abstract

Pinocembrin (PB; 5,7-dihydroxyflavanone) is found in propolis and exhibits antioxidant activity in several experimental models. The antioxidant capacity of PB is associated with the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. The Nrf2/ARE axis mediates the expression of antioxidant and detoxifying enzymes, such as glutathione peroxidase (GPx), glutathione reductase (GR), heme oxygenase-1 (HO-1), and the catalytic (GCLC) and regulatory (GCLM) subunits of the rate-limiting enzyme in the synthesis of glutathione (GSH), γ-glutamate-cysteine ligase (γ-GCL). Nonetheless, it is not clear how PB exerts mitochondrial protection in mammalian cells. Human neuroblastoma SH-SY5Y cells were pretreated (4 h) with PB (0–25 µM) and then exposed to methylglyoxal (MG; 500 µM) for further 24 h. Mitochondria were isolated by differential centrifugation. PB (25 µM) provided mitochondrial protection (decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes; decreased mitochondrial free radical production; enhanced the content of GSH in mitochondria; rescued mitochondrial membrane potential—MMP) and blocked MG-triggered cell death by a mechanism dependent on the activation of the extracellular-related kinase (Erk1/2) and consequent upregulation of Nrf2. PB increased the levels of GPx, GR, HO-1, and mitochondrial GSH. The PB-induced effects were suppressed by silencing of Nrf2 with siRNA. Therefore, PB activated the Erk1/2–Nrf2 signaling pathway resulting in mitochondrial protection in SH-SY5Y cells exposed to MG. Our work shows that PB is a strong candidate to figure among mitochondria-focusing agents with pharmacological potential.

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Acknowledgements

This work was supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq). GCF receives a “Bolsa Produtividade em Pesquisa”. GCF is supported by Edital APQ1/FAPERJ.

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Authors and Affiliations

  1. Department of Chemistry/ICET, Federal University of Mato Grosso (UFMT, Av. Fernando Corrêa da Costa, 2367, Cuiaba, MT, CEP 78060-900, Brazil

    Marcos Roberto de Oliveira

  2. Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil

    Alessandra Peres

  3. Centro de Pesquisa da Pós-Graduação, Centro Universitário Metodista IPA, Porto Alegre, Brazil

    Alessandra Peres

  4. Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Gustavo Costa Ferreira

Authors
  1. Marcos Roberto de Oliveira
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  2. Alessandra Peres
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  3. Gustavo Costa Ferreira
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Correspondence to Marcos Roberto de Oliveira.

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Electronic supplementary material

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11064_2016_2140_MOESM1_ESM.pdf

Supplementary material 1 Figure S1. A pretreatment with pinocembrin (PB) at 1–25 μM for 4 h ameliorates (a) cell viability and suppressed (b) cytotoxicity in human neuroblastoma SH-SY5Y cells exposed to methylglyoxal (MG) for additional 24 h. The results 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 MG-treated cells, **p < 0.01 different from MG-treated cells (PDF 92 KB)

11064_2016_2140_MOESM2_ESM.pdf

Supplementary material 2 Figure S2. Silencing of Nrf2 by using siRNA targeting Nrf2 in human neuroblastoma SH-SY5Y cells. Cells were further exposed to pinocembrin (PB) at 25 µM for 12 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, a p < 0.05 vs the control group, b p < 0.05 vs PB-treated cells transfected with negative control (NC) siRNA (PDF 102 KB)

11064_2016_2140_MOESM3_ESM.pdf

Supplementary material 3 Figure S3. The effects of a treatment with pinocembrin (25 µM) for different periods (0–24 h) on the cellular contents of a glutamate-cysteine ligase modifier subunit (GCLM), b glutamate-cysteine ligase catalytic subunit (GCLC), c glutathione peroxidase (GPx), and d glutathione reductase (GR) in human neuroblastoma SH-SY5Y cells. 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 < 0.01 vs the control group (PDF 85 KB)

11064_2016_2140_MOESM4_ESM.pdf

Supplementary material 4 Figure S4. The effects of a treatment with pinocembrin (25 µM) for different periods (0–24 h) on the cellular contents of heme oxygenase-1 (HO-1) in human neuroblastoma SH-SY5Y cells. 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 < 0.01 vs the control group (PDF 99 KB)

11064_2016_2140_MOESM5_ESM.pdf

Supplementary material 5 Figure S5. The effects of a treatment with pinocembrin (PB) at varying concentrations (0–25 µM) for 12 h on the nuclear Nrf2 levels in human neuroblastoma SH-SY5Y cells (a). The time-dependent (0–12 h) effects of pinocembrin at 25 µM on the nuclear Nrf2 content (b). 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 < 0.01 vs the control group (PDF 103 KB)

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de Oliveira, M.R., Peres, A. & Ferreira, G.C. Pinocembrin Attenuates Mitochondrial Dysfunction in Human Neuroblastoma SH-SY5Y Cells Exposed to Methylglyoxal: Role for the Erk1/2–Nrf2 Signaling Pathway. Neurochem Res 42, 1057–1072 (2017). https://doi.org/10.1007/s11064-016-2140-5

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  • DOI: https://doi.org/10.1007/s11064-016-2140-5

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