Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway
Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/12/3/556 |
| _version_ | 1797613890272493568 |
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| author | Sarah Naguib Carlisle R. DeJulius Jon R. Backstrom Ameer A. Haider John M. Ang Andrew M. Boal David J. Calkins Craig L. Duvall Tonia S. Rex |
| author_facet | Sarah Naguib Carlisle R. DeJulius Jon R. Backstrom Ameer A. Haider John M. Ang Andrew M. Boal David J. Calkins Craig L. Duvall Tonia S. Rex |
| author_sort | Sarah Naguib |
| collection | DOAJ |
| description | Erythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway that controls the expression of antioxidant proteins is the NRF2/ARE pathway. This pathway is activated endogenously after elevation of intraocular pressure (IOP) and contributes to the slow onset of pathology in glaucoma. In this study, we explored if sustained release of EPO-R76E in the eye would activate the NRF2/ARE pathway and if this pathway was key to its neuroprotective activity. Treatment with PLGA.EPO-E76E prevented increases in retinal superoxide levels in vivo, and caused phosphorylation of NRF2 and upregulation of antioxidants. Further, EPO-R76E activates NRF2 via phosphorylation by the MAPK pathway rather than the PI3K/Akt pathway, used by the endogenous antioxidant response to elevated IOP. |
| first_indexed | 2024-03-11T07:01:04Z |
| format | Article |
| id | doaj.art-f425def142764bd78d4e216706b866ad |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T07:01:04Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-f425def142764bd78d4e216706b866ad2023-11-17T09:16:27ZengMDPI AGAntioxidants2076-39212023-02-0112355610.3390/antiox12030556Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE PathwaySarah Naguib0Carlisle R. DeJulius1Jon R. Backstrom2Ameer A. Haider3John M. Ang4Andrew M. Boal5David J. Calkins6Craig L. Duvall7Tonia S. Rex8Neuroscience Program, Vanderbilt University, Nashville, TN 37232, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USAVanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USANeuroscience Program, Vanderbilt University, Nashville, TN 37232, USANeuroscience Program, Vanderbilt University, Nashville, TN 37232, USANeuroscience Program, Vanderbilt University, Nashville, TN 37232, USANeuroscience Program, Vanderbilt University, Nashville, TN 37232, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USANeuroscience Program, Vanderbilt University, Nashville, TN 37232, USAErythropoietin (EPO) is neuroprotective in multiple models of neurodegenerative diseases, including glaucoma. EPO-R76E retains the neuroprotective effects of EPO but diminishes the effects on hematocrit. Treatment with EPO-R76E in a glaucoma model increases expression of antioxidant proteins and is neuroprotective. A major pathway that controls the expression of antioxidant proteins is the NRF2/ARE pathway. This pathway is activated endogenously after elevation of intraocular pressure (IOP) and contributes to the slow onset of pathology in glaucoma. In this study, we explored if sustained release of EPO-R76E in the eye would activate the NRF2/ARE pathway and if this pathway was key to its neuroprotective activity. Treatment with PLGA.EPO-E76E prevented increases in retinal superoxide levels in vivo, and caused phosphorylation of NRF2 and upregulation of antioxidants. Further, EPO-R76E activates NRF2 via phosphorylation by the MAPK pathway rather than the PI3K/Akt pathway, used by the endogenous antioxidant response to elevated IOP.https://www.mdpi.com/2076-3921/12/3/556NRF2antioxidantglaucomaretinal ganglion cellneuroprotectionneurodegeneration |
| spellingShingle | Sarah Naguib Carlisle R. DeJulius Jon R. Backstrom Ameer A. Haider John M. Ang Andrew M. Boal David J. Calkins Craig L. Duvall Tonia S. Rex Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway Antioxidants NRF2 antioxidant glaucoma retinal ganglion cell neuroprotection neurodegeneration |
| title | Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway |
| title_full | Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway |
| title_fullStr | Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway |
| title_full_unstemmed | Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway |
| title_short | Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway |
| title_sort | intraocular sustained release of epo r76e mitigates glaucoma pathogenesis by activating the nrf2 are pathway |
| topic | NRF2 antioxidant glaucoma retinal ganglion cell neuroprotection neurodegeneration |
| url | https://www.mdpi.com/2076-3921/12/3/556 |
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