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Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro

Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to str...

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Autores principales: Sutherland, Brad A., Hadley, Gina, Alexopoulou, Zoi, Lodge, Tiffany A., Neuhaus, Ain A., Couch, Yvonne, Kalajian, Nareg, Morten, Karl J., Buchan, Alastair M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512098/
https://www.ncbi.nlm.nih.gov/pubmed/33013673
http://dx.doi.org/10.3389/fneur.2020.01023
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author Sutherland, Brad A.
Hadley, Gina
Alexopoulou, Zoi
Lodge, Tiffany A.
Neuhaus, Ain A.
Couch, Yvonne
Kalajian, Nareg
Morten, Karl J.
Buchan, Alastair M.
author_facet Sutherland, Brad A.
Hadley, Gina
Alexopoulou, Zoi
Lodge, Tiffany A.
Neuhaus, Ain A.
Couch, Yvonne
Kalajian, Nareg
Morten, Karl J.
Buchan, Alastair M.
author_sort Sutherland, Brad A.
collection PubMed
description Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7–10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 μM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling.
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spelling pubmed-75120982020-10-02 Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro Sutherland, Brad A. Hadley, Gina Alexopoulou, Zoi Lodge, Tiffany A. Neuhaus, Ain A. Couch, Yvonne Kalajian, Nareg Morten, Karl J. Buchan, Alastair M. Front Neurol Neurology Age-related neuronal dysfunction can be overcome by circulating factors present in young blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declines with age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Given that age increases susceptibility to stroke, we hypothesized that GDF-11 may be directly protective to neurons following ischemia. Primary cortical neurons were isolated from E18 Wistar rat embryos and cultured for 7–10 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellTox™ green cytotoxicity assays. 40 ng/mL GDF-11 administration during 2 h OGD significantly increased neuronal death following 24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 h OGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did not alter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatment had increased neuronal death which remained raised at 24 h. Co-treatment of 1 μM SB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicity after 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increase neuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity was also exhibited following neuronal exposure to hydrogen peroxide. These results reveal for the first time that GDF-11 is neurotoxic to primary neurons in the acute phase of simulated stroke through primarily ALK4 receptor signaling. Frontiers Media S.A. 2020-09-10 /pmc/articles/PMC7512098/ /pubmed/33013673 http://dx.doi.org/10.3389/fneur.2020.01023 Text en Copyright © 2020 Sutherland, Hadley, Alexopoulou, Lodge, Neuhaus, Couch, Kalajian, Morten and Buchan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Sutherland, Brad A.
Hadley, Gina
Alexopoulou, Zoi
Lodge, Tiffany A.
Neuhaus, Ain A.
Couch, Yvonne
Kalajian, Nareg
Morten, Karl J.
Buchan, Alastair M.
Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title_full Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title_fullStr Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title_full_unstemmed Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title_short Growth Differentiation Factor-11 Causes Neurotoxicity During Ischemia in vitro
title_sort growth differentiation factor-11 causes neurotoxicity during ischemia in vitro
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512098/
https://www.ncbi.nlm.nih.gov/pubmed/33013673
http://dx.doi.org/10.3389/fneur.2020.01023
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