Naguib Sarah, DeJulius Carlisle R, Backstrom Jon R, Haider Ameer A, Ang John M, Boal Andrew M, Calkins David J, Duvall Craig L, Rex Tonia S
Neuroscience Program, Vanderbilt University, Nashville, TN 37232, USA.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
Antioxidants (Basel). 2023 Feb 23;12(3):556. doi: 10.3390/antiox12030556.
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.
促红细胞生成素（EPO）在包括青光眼在内的多种神经退行性疾病模型中具有神经保护作用。EPO-R76E保留了EPO的神经保护作用，但减弱了对血细胞比容的影响。在青光眼模型中用EPO-R76E治疗可增加抗氧化蛋白的表达并具有神经保护作用。控制抗氧化蛋白表达的一条主要途径是NRF2/ARE途径。该途径在眼内压（IOP）升高后内源性激活，并导致青光眼病理变化的缓慢发生。在本研究中，我们探讨了EPO-R76E在眼内的持续释放是否会激活NRF2/ARE途径，以及该途径是否是其神经保护活性的关键。用PLGA.EPO-E76E治疗可防止体内视网膜超氧化物水平升高，并导致NRF2磷酸化和抗氧化剂上调。此外，EPO-R76E通过丝裂原活化蛋白激酶（MAPK）途径而非内源性抗氧化反应对升高的IOP所使用的磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）途径进行磷酸化来激活NRF2。
