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New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells

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Abstract

Probucol, a hypocholesterolemic compound, is neuroprotective in several models of neurodegenerative diseases but has serious adverse effects in vivo. We now describe the design and synthesis of two new probucol analogues that protect against glutamate-induced oxidative cell death, also known as ferroptosis, in cultured mouse hippocampal (HT22) cells and in primary cortical neurons, while probucol did not show any protective effect. Treatment with both compounds did not affect glutathione depletion but still significantly decreased glutamate-induced production of oxidants, mitochondrial superoxide generation, and mitochondrial hyperpolarization in HT22 cells. Both compounds increase glutathione peroxidase (GPx) 1 levels and GPx activity, also exhibiting protection against RSL3, a GPx4 inactivator. These two compounds are therefore potent activators of GPx activity making further studies of their neuroprotective activity in vivo worthwhile.

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Abbreviations

3-NA:

3-Nitropropionic acid

6-OHDA:

6-Hydroxydopamine

BSO:

Buthionine sulfoximine

CAT:

Catalase

CTB:

CellTiter-Blue

GCL:

Glycine cysteine ligase

DCFH-DA:

2′,7′-Dichlorofluorescein diacetate

DMEM:

Dulbecco’s Modified Eagle Medium

DMSO:

Dimethyl sulfoxide

ETS:

Electron transfer system

FBS:

Fetal bovine serum

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

Glu:

Glutamate

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

HBSS:

Hank’s balanced salt solution

MeHg:

Methylmercury

MMP:

Mitochondrial membrane potential

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MSA:

β-Mercaptosuccinic acid

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

NPSH:

Non-protein thiol

O2•− :

Anion superoxide

PB:

Probucol

PI:

Propidium iodide

SOD:

Superoxide dismutase

STZ:

Streptozotocin

tBuOOH:

tert-butyl hydroperoxide

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Acknowledgments

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). We also thank the Academic Exchange Fellowships conceded by CAPES (process 88881.134820/2016-01) and Deutscher Akademischer Austauschdienst (DAAD). We are also grateful to the Laboratório Multiusuário de Estudos em Biologia at the Universidade Federal de Santa Catarina (LAMEB/UFSC) for providing its infrastructure for carrying out biochemical analysis.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Diones Caeran Bueno, Viviane de Souza, Rafaela Rafognatto Andreguetti, Aline Aita Naime, Mark William Lopes & Marcelo Farina

  2. Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Diones Caeran Bueno, Partha Narayan Dey, Verena Wüllner & Axel Methner

  3. Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil

    Rômulo Faria Santos Canto

  4. Department of Chemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Flávio Augusto Rocha Barbosa & Antônio Luiz Braga

Authors
  1. Diones Caeran Bueno
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  2. Rômulo Faria Santos Canto
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  3. Viviane de Souza
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  4. Rafaela Rafognatto Andreguetti
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  5. Flávio Augusto Rocha Barbosa
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  6. Aline Aita Naime
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  7. Partha Narayan Dey
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  8. Verena Wüllner
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  9. Mark William Lopes
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  10. Antônio Luiz Braga
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  11. Axel Methner
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  12. Marcelo Farina
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Corresponding authors

Correspondence to Diones Caeran Bueno, Axel Methner or Marcelo Farina.

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Bueno, D.C., Canto, R.F.S., de Souza, V. et al. New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells. Mol Neurobiol 57, 3273–3290 (2020). https://doi.org/10.1007/s12035-020-01956-9

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  • DOI: https://doi.org/10.1007/s12035-020-01956-9

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