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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2025-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Amanda Candida da Rocha Oliveira |
| collection | DOAJ |
| description | <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. |
| format | Article |
| id | doaj-art-4952b4f6e9124cffb6d4f4fc19da0c9d |
| institution | DOAJ |
| issn | 2076-3425 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-4952b4f6e9124cffb6d4f4fc19da0c9d2025-08-20T02:44:55ZengMDPI AGBrain Sciences2076-34252025-01-0115212310.3390/brainsci15020123Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling PathwaysAmanda Candida da Rocha Oliveira0Camila Saggioro Figueiredo1Ícaro Raony2Juliana Salles Von-Held-Ventura3Marcelo Gomes Granja4Thalita Mázala-de-Oliveira5Vinícius Henrique Pedrosa-Soares6Aline Araujo dos Santos7Elizabeth Giestal-de-Araujo8Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, BrazilDepartment of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, BrazilInstitute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, BrazilDepartment of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, BrazilResearch, Innovation, and Surveillance Center for COVID-19 and Health Emergencies, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, BrazilDepartment of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, BrazilDepartment of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, BrazilNational Institute of Science and Technology on Neuroimmunomodulation—INCT-NIM, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, BrazilDepartment of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niteroi 24020-141, Brazil<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.https://www.mdpi.com/2076-3425/15/2/123brain-derived neurotrophic factorcytokinegrowth factorsteroid hormoneinterleukin-1βmatrix metalloproteinase-9 |
| spellingShingle | 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 Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways Brain Sciences brain-derived neurotrophic factor cytokine growth factor steroid hormone interleukin-1β matrix metalloproteinase-9 |
| title | Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways |
| title_full | Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways |
| title_fullStr | Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways |
| title_full_unstemmed | Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways |
| title_short | Ouabain Counteracts Retinal Ganglion Cell Death Through Modulation of BDNF and IL-1 Signaling Pathways |
| title_sort | ouabain counteracts retinal ganglion cell death through modulation of bdnf and il 1 signaling pathways |
| topic | brain-derived neurotrophic factor cytokine growth factor steroid hormone interleukin-1β matrix metalloproteinase-9 |
| url | https://www.mdpi.com/2076-3425/15/2/123 |
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