2. Academic Validation
  3. New Probucol Analogues Inhibit Ferroptosis, Improve Mitochondrial Parameters, and Induce Glutathione Peroxidase in HT22 Cells

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

  • Mol Neurobiol. 2020 Aug;57(8):3273-3290. doi: 10.1007/s12035-020-01956-9.
Diones Caeran Bueno 1 2,  Rômulo Faria Santos Canto 3,  Viviane de Souza 4,  Rafaela Rafognatto Andreguetti 4,  Flávio Augusto Rocha Barbosa 5,  Aline Aita Naime 4,  Partha Narayan Dey 6,  Verena Wüllner 6,  Mark William Lopes 4,  Antônio Luiz Braga 5,  Axel Methner 7,  Marcelo Farina 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil. [email protected].
  • 2 Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. [email protected].
  • 3 Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil.
  • 4 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
  • 5 Department of Chemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
  • 6 Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
  • 7 Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. [email protected].
  • 8 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil. [email protected].
PMID: 32514861 DOI: 10.1007/s12035-020-01956-9
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.

Keywords

Antioxidant; Ferroptosis; Glutathione peroxidase; HT22; Oxytosis; Probucol.

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