General Description

Erythropoietin exhibits neuroprotective functions through various signaling pathways, contributing to cognition improvement, neurogenesis, and tissue protection beyond its hematopoietic effects. In the context of glaucoma, Erythropoietin has shown promising therapeutic effects by promoting RGC survival, regeneration, and protection through pathways like PI3K/Akt and JAK2/STAT3. However, Erythropoietin therapy is associated with potential side effects such as increased blood viscosity, polycythemia, neurological issues, and a possible link to tumor growth. Close monitoring, dosage adjustments, and careful consideration of risks are essential for the safe and effective use of Erythropoietin in patients, especially those with specific medical conditions.

Figure 1. Erythropoietin

Neuroprotective Function

More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure–function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new “designer” drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.¹

Therapeutic Effect in Glaucoma

Glaucoma, the second leading cause of blindness worldwide, is a progressive and multifactorial optic neuropathy characterized by the loss of retinal ganglion cells (RGCs). The number of patients with glaucoma worldwide is estimated to reach 111.8 million by 2040, with an especially higher impact in Asia and Africa. Recently, glaucoma is regarded as a neurodegenerative disorder involving the eye and brain with some common traits with Alzheimer's disease (AD) and other tauopathies. 

Erythropoietin (EPO), a hematopoietic cytokine, has been studied for its potential therapeutic effects in many neurodegenerative diseases, including Parkinson’s disease, AD, amyotrophic lateral sclerosis, spinal cord injury, brain ischemia, hypoxia, and hyperoxia. In ophthalmology, the EPO receptor (EPOR) is expressed in human retinal tissues, such as the photoreceptor cells, retinal pigment epithelium, and RGC layer. Emerging evidence has suggested a potent neuroprotective effect of EPO in the brain and retina. In cultured retinal neurocytes, it promotes neurite outgrowth in a dose-dependent manner. Additionally, it increases the survival and decreases the apoptosis of retinal neurocytes from glutamate-induced cytotoxicity. Tezel et al. showed a two-fold upregulation of the hemoglobin (Hb) expression in ocular hypertensive rat eyes and glaucomatous human donor eyes. The hypoxia-inducible EPO signaling was found to regulate the expression of Hb in the macroglia and RGCs and was suggested to be an intrinsic protective mechanism of neuronal cells. Previous studies have also found a significantly higher aqueous levels of EPO in primary open-angle glaucoma, acute and chronic primary angle-closure glaucoma, neovascular glaucoma, and pseudoexfoliative glaucoma. Tissue hypoxia, the major stimulating factor of Erythropoietin production, was also found in the retina and optic nerve head of glaucomatous eyes, and hypoxic signaling transduction is considered to be a likely component of the pathogenic mechanisms of glaucomatous neurodegeneration. Consequently, there is a growing interest in the study of the potential therapeutic effects of EPO in glaucoma patients.²

Reference

1. Bhoopalan SV, Huang LJ, Weiss MJ. Erythropoietin regulation of red blood cell production: from bench to bedside and back. F1000Res. 2020; 9: F1000 Faculty Rev-1153.

2. Lin TY, Lai YF, Chen YH, Lu DW. The Latest Evidence of Erythropoietin in the Treatment of Glaucoma. Int J Mol Sci. 2022; 23(24): 16038.