Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways

Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways

<b>Background:</b> Ouabain is a steroid hormone that binds to the sodium pump (Na<sup>+</sup>, K<sup>+</sup>-ATPase) at physiological (nanomolar) concentrations, activating different signaling pathways. This interaction has been shown to prevent the axotomy-induce...

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Main Authors: Amanda Candida da Rocha Oliveira, Camila Saggioro Figueiredo, Ícaro Raony, Juliana Salles Von-Held-Ventura, Marcelo Gomes Granja, Thalita Mázala-de-Oliveira, Vinícius Henrique Pedrosa-Soares, Aline Araujo dos Santos, Elizabeth Giestal-de-Araujo
Format: Article
Language:English
Published: MDPI AG 2025-01-01
Series:Brain Sciences
Subjects:
brain-derived neurotrophic factor
cytokine
growth factor
steroid hormone
interleukin-1β
matrix metalloproteinase-9
Online Access:https://www.mdpi.com/2076-3425/15/2/123
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Summary:<b>Background:</b> Ouabain is a steroid hormone that binds to the sodium pump (Na<sup>+</sup>, K<sup>+</sup>-ATPase) at physiological (nanomolar) concentrations, activating different signaling pathways. This interaction has been shown to prevent the axotomy-induced death of retinal ganglion cells (RGCs), although the underlying mechanisms remain unclear. <b>Objective:</b> In this study, we investigated potential mechanisms by which ouabain promotes RGC survival using primary cultures of rat neural retina. <b>Results:</b> Our findings indicate that ouabain regulates brain-derived neurotrophic factor (BDNF) signaling in retinal cells via matrix metalloproteinase-9-mediated processing of proBDNF to mature BDNF (mBDNF) and by increasing the phosphorylation of the mBDNF receptor, tropomyosin-related receptor kinase B. Ouabain also enhances the maturation of interleukin (IL)-1β through the increased activation of caspase-1, which mediates the processing of proIL-1β into IL-1β, and transiently upregulates both IL-1 receptor and IL-1 receptor antagonist (IL-1Ra). Treatment using either IL-1β or IL-1Ra alone is sufficient to enhance RGC survival similarly to that achieved with ouabain. Finally, we further show that ouabain prevents RGC death through a complex signaling mechanism shared by BDNF and IL-1β, which includes the activation of the Src and protein kinase C pathways. <b>Conclusions:</b> Collectively, these results suggest that ouabain stimulates the maturation and signaling of both BDNF and IL-1β, which act as key mediators of RGC survival.
ISSN:2076-3425

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