Research Models to Study Ferroptosis's Impact in Neurodegenerative Diseases

Inês Costa; Daniel José Barbosa; Vera Silva; Sofia Benfeito; Fernanda Borges; Fernando Remião; Renata Silva

doi:10.3390/pharmaceutics15051369

Research Models to Study Ferroptosis's Impact in Neurodegenerative Diseases

Pharmaceutics. 2023 Apr 29;15(5):1369. doi: 10.3390/pharmaceutics15051369.

Authors

Inês Costa^{1

2}, Daniel José Barbosa^{3

4}, Vera Silva^{1

2

5}, Sofia Benfeito⁵, Fernanda Borges⁵, Fernando Remião^{1

2}, Renata Silva^{1

2}

Affiliations

¹ Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
² UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
³ TOXRUN-Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal.
⁴ Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal.
⁵ CIQUP-IMS-Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.

Abstract

Ferroptosis is a type of regulated cell death promoted by the appearance of oxidative perturbations in the intracellular microenvironment constitutively controlled by glutathione peroxidase 4 (GPX4). It is characterized by increased production of reactive oxygen species, intracellular iron accumulation, lipid peroxidation, inhibition of system Xc-, glutathione depletion, and decreased GPX4 activity. Several pieces of evidence support the involvement of ferroptosis in distinct neurodegenerative diseases. In vitro and in vivo models allow a reliable transition to clinical studies. Several in vitro models, including differentiated SH-SY5Y and PC12 cells, among others, have been used to investigate the pathophysiological mechanisms of distinct neurodegenerative diseases, including ferroptosis. In addition, they can be useful in the development of potential ferroptosis inhibitors that can be used as disease-modifying drugs for the treatment of such diseases. On the other hand, in vivo models based on the manipulation of rodents and invertebrate animals, such as Drosophila melanogaster, Caenorhabditis elegans, and zebrafish, have been increasingly used for research in neurodegeneration. This work provides an up-to-date review of the main in vitro and in vivo models that can be used to evaluate ferroptosis in the most prevalent neurodegenerative diseases, and to explore potential new drug targets and novel drug candidates for effective disease-modifying therapies.

Keywords: ferroptosis; in vitro models; in vivo models; neurodegeneration; neurodegenerative diseases.

Publication types

Review

Grants and funding

This work was financed by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB. In addition, this work was also funded by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and national funds by FCT—Foundation for Science and Technology under research grants (Grants UIDB/00081/2020 (CIQUP), PTDC/MED-QUI/29164/2017–POCI-01- 0145-FEDER-29164, LA/P/0056/2020 (IMS) and PT-OPENSCREEN-NORTE-01-0145-FEDER-085468 projects, and from CESPU, in the scope of the project Mddemy-GI2-CESPU-2022.