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Pinocembrin Suppresses H2O2-Induced Mitochondrial Dysfunction by a Mechanism Dependent on the Nrf2/HO-1 Axis in SH-SY5Y Cells

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Abstract

Mitochondria are susceptible to redox impairment, which has been associated with neurodegeneration. These organelles are both a source and target of reactive species. In that context, there is increasing interest in finding natural compounds that modulate mitochondrial function and mitochondria-related signaling in order to prevent or to treat diseases involving mitochondrial impairment. Herein, we investigated whether and how pinocembrin (PB) would prevent mitochondrial dysfunction elicited by the exposure of human neuroblastoma SH-SY5Y cells to hydrogen peroxide (H2O2). PB (25 μM) was administrated for 4 h before H2O2 treatment (300 μM for 24 h). PB prevented H2O2-induced loss of cell viability mitochondrial depolarization in SH-SY5Y cells. PB also attenuated redox impairment in mitochondrial membranes. The production of superoxide anion radical (O2 −•) and nitric oxide (NO•) was alleviated by PB in cells exposed to H2O2. PB suppressed the H2O2-induced inhibition of the tricarboxylic acid (TCA) cycle enzymes aconitase, α-ketoglutarate dehydrogenase, and succinate dehydrogenase. Furthermore, PB induced anti-inflammatory effects by abolishing the H2O2-dependent activation of the nuclear factor-κB (NF-κB) and upregulation of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). The PB-induced antioxidant and anti-inflammatory effects are dependent on the heme oxygenate-1 (HO-1) enzyme and on the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), since HO-1 inhibition (with 0.5 μM ZnPP IX) or Nrf2 silencing (with small interfering RNA (siRNA)) abolished the effects of PB. Overall, PB afforded cytoprotection by the Nrf2/HO-1 axis in H2O2-treated SH-SY5Y cells.

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Acknowledgments

GCF is supported by Edital APQ1/FAPERJ and receives a “Produtividade em Pesquisa do CNPq - Nível 2” fellow. FBB is supported by FOPESQ/UFF. This work was supported by CNPq.

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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, 78060-900, Brazil

    Marcos Roberto de Oliveira

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

    Gustavo da Costa Ferreira

  3. Universidade Federal Fluminense, Rio de Janeiro, RJ, Brazil

    Flávia Bittencourt Brasil

  4. Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil

    Alessandra Peres

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

    Alessandra Peres

Authors
  1. Marcos Roberto de Oliveira
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  2. Gustavo da Costa Ferreira
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  3. Flávia Bittencourt Brasil
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  4. Alessandra Peres
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Correspondence to Marcos Roberto de Oliveira.

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Electronic supplementary material

Figure S1

The effect of hydrogen peroxide (H2O2) at 25–400 μM for 24 h on the viability of SH-SY5Y cells. Data are shown 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 different from the control group. (PDF 96 kb)

Figure S2

The effects of a pretreatment with pinocembrin (PB) at 1–25 μM for 4 h on the viability of SH-SY5Y cells exposed to hydrogen peroxide (H2O2) for further 24 h. Data are shown 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 different from the control group; * p < 0.05 different from the cells treated with H2O2; ** p < 0.01 different from the cells treated with H2O2. (PDF 96 kb)

Figure S3

The effects of the inhibition of the nuclear factor-κB (NF-κB) on the levels of (A) interleukin-1β (IL-1β) and (B) tumor necrosis factor-α (TNF-α). The effect of SN50 on the activity of NF-κB is shown in (C). The cells were treated with SN50 at 0.5 μM for 1 h prior administration of H2O2 at 300 μM for further 24 h. Data are shown 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 different from the control group; ** p < 0.05 different from the cells treated with H2O2. (PDF 185 kb)

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de Oliveira, M.R., da Costa Ferreira, G., Brasil, F.B. et al. Pinocembrin Suppresses H2O2-Induced Mitochondrial Dysfunction by a Mechanism Dependent on the Nrf2/HO-1 Axis in SH-SY5Y Cells. Mol Neurobiol 55, 989–1003 (2018). https://doi.org/10.1007/s12035-016-0380-7

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