Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation

  • Ruth Liliám Quispe
  • Rômulo Faria Santos Canto
  • Michael Lorenz Jaramillo
  • Flavio Augusto Rocha Barbosa
  • Antônio Luiz Braga
  • Andreza Fabro de Bem
  • Marcelo Farina
Article

Abstract

Recent studies have shown that probucol (PB), a hipocholesterolemic agent with antioxidant and anti-inflammatory properties, presents neuroprotective properties. On the other hand, adverse effects have limited PB’s clinical application. Thus, the search for PB derivatives with no or less adverse effects has been a topic of research. In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicity induced by tert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48 h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondrial dysfunction. Of note, RC513 significantly increased glutathione peroxidase (GPx) activity and mRNA expression of GPx1, a key enzyme involved in peroxide detoxification. The use of mercaptosuccinic acid, an inhibitor of GPx, significantly decreased the protective activity of RC513 against tBuOOH-induced cytotoxicity in HT22 cells, highlighting the importance of GPx upregulation in the observed protection. In summary, the results showed a significant protective activity of a novel PB derivative against tBuOOH-induced oxidative stress and mitochondrial dysfunction, which was related to the upregulation of GPx. Our results point to RC513 as a promising neuroprotective molecule, even though studies concerning potential beneficial effects and safety aspects of RC513 under in vivo conditions are well warranted.

Keywords

Probucol derivative Glutathione peroxidase Mitochondrial dysfunction HT22 cells tBuOOH 

Abbreviations

PB

Probucol

GPx

Glutathione peroxidase

SH

Glutathione

GR

Glutathione reductase

NADPH

β-Nicotinamide adenine dinucleotide phosphate sodium salt reduced

DMSO

Dimethyl sulfoxide

MTT

3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide

PI

Propidium iodide

DCFH2-DA

2′,7′-Dichlorofluorescein diacetate

tBuOOH

tert-Butyl hydroperoxide

MS

Mercaptosuccinic acid

DTNB

5,5′-Dithiobis(2-nitrobenzoic acid)

FCCP

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

DMEM

Dulbecco’s modified Eagle’s medium

FBS

Fetal bovine serum

HBSS

Hank’s balanced salt solution

NPSH

Non-protein thiols

Notes

Acknowledgements

The financial support by (i) Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), (ii) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and (iii) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) is gratefully acknowledged. MF, AFB, and ALB are CNPq fellowship recipients. Part of the work was performed with the support from LAMEB (Laboratório Multiusuário de Ciências Biológicas—UFSC), whose technicians are gratefully acknowledged. The authors are also thankful to CEBIME-UFSC for mass analyses.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_939_Fig9_ESM.gif (24 kb)
Fig. S1

Antioxidant activity of RC513. RC513 (25 μM) or trolox (positive control) were incubated with the stable radical DPPH (500 μM) during 30 min at room temperature. Expressed results as percentage of antioxidant activity. Values are represented as mean ± SEM (n = 3). ** indicates statistical difference (p < 0.01) by Student’s t-test. (GIF 24 kb)

12035_2018_939_MOESM1_ESM.tif (1.8 mb)
High Resolution Image (TIFF 1849 kb)
12035_2018_939_MOESM2_ESM.pdf (160 kb)
Table S1 Temporal expression of Tr2 (thioredoxin reductase 2) gene in RC513-treated HT22 cells. HT22 cells were treated with 2 μM RC513 or vehicle during 3 h, 6 h, 12 h and 24 h. Transcripts levels of Tr2 were normalized with Gapdh gene and calculated by the 2-ΔΔCT method. Values are represented as mean ± SEM (n = 4) (PDF 160 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Programa de Pós-Graduação em NeurociênciasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.Departamento de FarmacociênciasUniversidade Federal de Ciências da Saúde de Porto AlegrePorto AlegreBrazil
  4. 4.Departamento de Biologia Celular, Embriologia e GenéticaUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  5. 5.Departamento de Química, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil

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