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Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators

Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer’s disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has...

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Autores principales: Jakaria, Md., Belaidi, Abdel A., Southon, Adam, Dent, Krista A., Lane, Darius J. R., Bush, Ashley I., Ayton, Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784883/
https://www.ncbi.nlm.nih.gov/pubmed/36555849
http://dx.doi.org/10.3390/ijms232416205
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author Jakaria, Md.
Belaidi, Abdel A.
Southon, Adam
Dent, Krista A.
Lane, Darius J. R.
Bush, Ashley I.
Ayton, Scott
author_facet Jakaria, Md.
Belaidi, Abdel A.
Southon, Adam
Dent, Krista A.
Lane, Darius J. R.
Bush, Ashley I.
Ayton, Scott
author_sort Jakaria, Md.
collection PubMed
description Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer’s disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases.
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spelling pubmed-97848832022-12-24 Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators Jakaria, Md. Belaidi, Abdel A. Southon, Adam Dent, Krista A. Lane, Darius J. R. Bush, Ashley I. Ayton, Scott Int J Mol Sci Article Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer’s disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases. MDPI 2022-12-19 /pmc/articles/PMC9784883/ /pubmed/36555849 http://dx.doi.org/10.3390/ijms232416205 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jakaria, Md.
Belaidi, Abdel A.
Southon, Adam
Dent, Krista A.
Lane, Darius J. R.
Bush, Ashley I.
Ayton, Scott
Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title_full Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title_fullStr Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title_full_unstemmed Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title_short Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators
title_sort receptor-independent anti-ferroptotic activity of trkb modulators
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784883/
https://www.ncbi.nlm.nih.gov/pubmed/36555849
http://dx.doi.org/10.3390/ijms232416205
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