Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat

Abstract

Pinocembrin (PB; 5,7-dihydroxyflavanone; C15H12O4) is a flavonoid found in propolis and exerts antioxidant, anti-inflammatory, and antimicrobial effects. Furthermore, PB has been studied as a neuroprotective agent. However, it remains to be understood whether and how PB would induce mitochondrial protection in mammalian cells. Therefore, we investigated here the mechanism involved in the protective effects elicited by PB in paraquat (PQ; 100 μM)-treated SH-SY5Y neuroblastoma cells. PB (25 μM) pretreatment (for 4 h) downregulated the levels of Bcl-2-associated X protein (Bax), blocked the release of cytochrome c to the cytosol, and inhibited the PQ-induced activation of caspase-9 and caspase-3. Besides, PB prevented mitochondrial dysfunction by suppressing the PQ-elicited inhibition of complexes I and V. Moreover, PB abrogated the loss of mitochondrial membrane potential (MMP) and the decline in ATP levels in the cells exposed to PQ. PB exerted antioxidant effects on mitochondria by decreasing the levels of redox impairment markers in mitochondrial membranes. Importantly, PB enhanced the levels of mitochondrial reduced glutathione (GSH). Upregulation of enzymes involved in the synthesis of GSH was seen in the cells exposed to PB. PB afforded mitochondrial protection by activating the extracellular signal-regulated kinase/nuclear factor erythroid 2-related factor 2 (Erk1/2-Nrf2) axis, since inhibition of Erk1/2 or silencing of Nrf2 abrogated these effects. Therefore, PB exerted mitochondrial and cellular protection by an Erk1/2-Nrf2-dependent mechanism.

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Acknowledgments

CSG is a recipient of a fellow of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Bolsista de Produtividade em Pesquisa 1D). This work was supported by the CNPq.

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Correspondence to Marcos Roberto de Oliveira.

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Figure S1

The effects of a pretreatment with pinocembrin (PB) at 1–25 μM for 4 h on the cell viability (A) and cytotoxicity (B) parameters of SH-SY5Y cells exposed to paraquat (PQ) for further 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 the control group, * p < 0.05 different from PQ-treated cells, ** p < 0.01 different from PQ-treated cells. (PDF 98 kb)

Figure S2

The effects of a pretreatment with pinocembrin (PB) at 1–25 μM for 4 h on the contents of Bcl-2 (A), Bax (B), cytosolic cytochrome c (cyt c) (C), and mitochondrial cyt c (D), and on the activities of caspase-9 (E) and caspase-3 (F) in SH-SY5Y cells exposed to paraquat (PQ) for further 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 different from control cells, # p < 0.05 different from PQ-treated cells. (PDF 89 kb)

Figure S3

The effects of a pretreatment with pinocembrin (PB) at 1–25 μM for 4 h on the levels of DNA fragmentation in SH-SY5Y cells exposed to paraquat (PQ) for further 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 different from control cells, # p < 0.05 different from PQ-treated cells. (PDF 82 kb)

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de Oliveira, M.R., Peres, A., Gama, C.S. et al. Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat. Mol Neurobiol 54, 6018–6031 (2017). https://doi.org/10.1007/s12035-016-0135-5

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Keywords

  • Pinocembrin
  • Mitochondria
  • Paraquat
  • Antioxidant
  • Nrf2