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Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro

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Sutherland, BA ORCID: 0000-0002-0791-0950, Hadley, G, Alexopoulou, Z, Lodge, TA, Neuhaus, AA, Couch, Y, Kalajian, N, Morten, KJ and Buchan, AM 2020 , 'Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro' , Frontiers in Neurology , pp. 1-8 , doi: 10.3389/fneur.2020.01023.

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Abstract

Age-related neuronal dysfunction can be overcome by circulating factors present inyoung blood. Growth differentiation factor-11 (GDF-11), a systemic factor that declineswith age, can reverse age-related dysfunction in brain, heart and skeletal muscle. Giventhat age increases susceptibility to stroke, we hypothesized that GDF-11 may be directlyprotective to neurons following ischemia. Primary cortical neurons were isolated fromE18 Wistar rat embryos and cultured for 7–10 days. Neurons were deprived of oxygenand glucose (OGD) to simulate ischemia. Neuronal death was assessed by lactatedehydrogenase, propidium iodide or CellToxTMgreen cytotoxicity assays. 40 ng/mLGDF-11 administration during 2 h OGD significantly increased neuronal death following24 h recovery. However, GDF-11 pre-treatment did not affect neuronal death during 2 hOGD. GDF-11 treatment during the 24 h recovery period after 2 h OGD also did notalter death. Real-time monitoring for 24 h revealed that by 2 h OGD, GDF-11 treatmenthad increased neuronal death which remained raised at 24 h. Co-treatment of 1µMSB431542 (ALK4/5/7 receptor inhibitor) with GDF-11 prevented GDF-11 neurotoxicityafter 2 h OGD and 24 h OGD. Transforming growth factor beta (TGFβ) did not increaseneuronal death to the same extent as GDF-11 following OGD. GDF-11 neurotoxicity wasalso exhibited following neuronal exposure to hydrogen peroxide. These results revealfor the first time that GDF-11 is neurotoxic to primary neurons in the acute phase ofsimulated stroke through primarily ALK4 receptor signaling.

Item Type: Article
Authors/Creators: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
Keywords: neurotoxicity, stroke, ischemia, growth differentiation factor-11, OGD, cell culture
Journal or Publication Title: Frontiers in Neurology
Publisher: Frontiers Research Foundation
ISSN: 1664-2295
DOI / ID Number: 10.3389/fneur.2020.01023
Copyright Information:

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/

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