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

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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Correspondence to Marcos Roberto de Oliveira.

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Supplementary material 1 Figure S1. A pretreatment with pinocembrin (PB) at 1–25 μM for 4 h ameliorates () 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)

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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, p < 0.05 vs the control group, b p < 0.05 vs PB-treated cells transfected with negative control (NC) siRNA (PDF 102 KB)

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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 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)

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)

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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 (). 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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Keywords

  • Pinocembrin
  • Mitochondria
  • Methylglyoxal
  • Antioxidant
  • Nrf2