Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1784857917678157824 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9784883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT jakariamd receptorindependentantiferroptoticactivityoftrkbmodulators AT belaidiabdela receptorindependentantiferroptoticactivityoftrkbmodulators AT southonadam receptorindependentantiferroptoticactivityoftrkbmodulators AT dentkristaa receptorindependentantiferroptoticactivityoftrkbmodulators AT lanedariusjr receptorindependentantiferroptoticactivityoftrkbmodulators AT bushashleyi receptorindependentantiferroptoticactivityoftrkbmodulators AT aytonscott receptorindependentantiferroptoticactivityoftrkbmodulators |