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Neurotoxicity Research

, Volume 36, Issue 3, pp 551–562 | Cite as

Carnosic Acid Pretreatment Attenuates Mitochondrial Dysfunction in SH-SY5Y Cells in an Experimental Model of Glutamate-Induced Excitotoxicity

  • Marcos Roberto de OliveiraEmail author
  • Adriane Ribeiro Duarte
  • Aline Lukasievicz Chenet
  • Fhelipe Jolner Souza de Almeida
  • Claudia Marlise Balbinotti Andrade
Original Article

Abstract

Mitochondria are the major site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, mitochondria produce most of the reactive oxygen species (ROS) in nucleated cells. Redox and bioenergetic abnormalities have been seen in mitochondria during the onset and progression of neurodegenerative diseases. In that context, excitotoxicity induced by glutamate (GLU) plays an important role in mediating neurotoxicity. Several drugs have been used in the treatment of diseases involving excitotoxicity. Nonetheless, some patients (20–30%) present drug resistance. Thus, it is necessary to find chemicals able to attenuate mitochondrial dysfunction in the case of excitotoxicity. In this work, we treated the human neuroblastoma SH-SY5Y cell line with the diterpene carnosic acid (CA) at 1 μM for 12 h prior to the exposure to GLU for further 24 h. We found that CA prevented the GLU-induced mitochondrion-related redox impairment and bioenergetic decline in SH-SY5Y cells. CA also downregulated the pro-apoptotic stimulus elicited by GLU in this experimental model. CA exerted mitochondrial protection by a mechanism associated with the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), since silencing of this protein with small interfering RNA (siRNA) suppressed the CA-induced protective effects. Future directions include investigating whether CA would be able to modulate mitochondrial function and/or dynamics in in vivo experimental models of excitotoxicity.

Keywords

Carnosic acid Glutamate Excitotoxicity Mitochondria Nrf2 Antioxidant 

Notes

Funding Information

This work was supported by CNPq (Edital Universal 2016). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Brazil) Finance Code 001 (ALC receives a CAPES Fellow (Bolsa de Mestrado)).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12640_2019_44_MOESM1_ESM.pdf (90 kb)
Figure S1 The effects of a pretreatment with CA at 1 μM for 12 h on Bax immunocontent (A), cytosolic cytochrome c content (B), mitochondrial cytochrome c content (C), caspase-9 activity (D), and caspase-3 activity (E) in SH-SY5Y cells exposed to glutamate (GLU) at 80 mM for further 24 h. The results are presented as the mean ± S.E.M. 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; # p < 0.05 vs GLU-treated cells. (PDF 90 kb)
12640_2019_44_MOESM2_ESM.pdf (5 kb)
Figure S2 The effects of CA at 1 μM for different periods on the activity of the transcription factor Nrf2. The results are presented as the mean ± S.E.M. 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. (PDF 4 kb)
12640_2019_44_MOESM3_ESM.pdf (6 kb)
Figure S3 The effects of Nrf2 siRNA (48 h) on the activity of the transcription factor Nrf2 in SH-SY5Y cells exposed to CA for 1 h. The results are presented as the mean ± S.E.M. 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; # p < 0.05 vs CA-treated cells transfected with negative control (NC) siRNA. (PDF 5 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Marcos Roberto de Oliveira
    • 1
    • 2
    • 3
    Email author
  • Adriane Ribeiro Duarte
    • 1
    • 2
  • Aline Lukasievicz Chenet
    • 1
    • 2
  • Fhelipe Jolner Souza de Almeida
    • 1
    • 3
  • Claudia Marlise Balbinotti Andrade
    • 1
    • 3
  1. 1.Grupo de Estudos em Neuroquímica e Neurobiologia de Moléculas BioativasUniversidade Federal de Mato Grosso (UFMT)CuiabaBrazil
  2. 2.Programa de Pós-Graduação em Química (PPGQ)Universidade Federal de Mato Grosso (UFMT)CuiabaBrazil
  3. 3.Programa de Pós-Graduação em Ciências da Saúde (PPGCS)Universidade Federal de Mato Grosso (UFMT)CuiabaBrazil

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