posted on 2023-05-20, 18:11authored byBrad SutherlandBrad Sutherland, Hadley, G, Alexopoulou, Z, Lodge, TA, Neuhaus, AA, Couch, Y, Kalajian, N, Morten, KJ, Buchan, AM
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 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 1µM 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.
Funding
National Health & Medical Research Council
History
Publication title
Frontiers in Neurology
Pagination
1-8
ISSN
1664-2295
Department/School
Tasmanian School of Medicine
Publisher
Frontiers Research Foundation
Place of publication
Switzerland
Rights 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/
Repository Status
Open
Socio-economic Objectives
Expanding knowledge in the biomedical and clinical sciences