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Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro

Citation

Sutherland, BA and Hadley, G and Alexopoulou, Z and Lodge, TA and Neuhaus, AA and Couch, Y and Kalajian, N and Morten, KJ and Buchan, AM, Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro, Frontiers in Neurology pp. 1-8. ISSN 1664-2295 (2020) [Refereed Article]


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Copyright Statement

Copyright 2020 Sutherland, Hadley, Alexopoulou, Lodge, Neuhaus, Couch, Kalajian, Morten and Buchan. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.3389/fneur.2020.01023

Abstract

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 710 days. Neurons were deprived of oxygen and glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactate dehydrogenase, propidium iodide or CellToxTMgreen 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 1M 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.

Item Details

Item Type:Refereed Article
Keywords:neurotoxicity, stroke, ischemia, growth differentiation factor-11, OGD, cell culture
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Cellular nervous system
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Sutherland, BA (Associate Professor Brad Sutherland)
ID Code:141100
Year Published:2020
Funding Support:National Health and Medical Research Council (APP1137776)
Web of Science® Times Cited:41
Deposited By:Office of the School of Medicine
Deposited On:2020-09-24
Last Modified:2021-04-21
Downloads:1 View Download Statistics

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