Erythropoietin, also known as EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood.

In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain's response to neuronal injury.

EPO is also involved in the wound healing process.

Robinson et al. tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition, and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in uteroplacental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood 1).

Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3β/beta-catenin signaling pathway in the EPO-mediated proliferation of glioma.

Methods: The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear beta-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed.

Results: The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3β and the expression of nuclear beta-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3β/beta-catenin pathway and proliferation were abolished by MK-2206.

Conclusions: Our study identified the AKT/GSK-3β/beta-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO 2).

Studies in animal models indicate that recombinant human erythropoietin (rhEPO) is very effective in enhancing neurological recovery after spinal cord injury (SCI).

Early administration of medications after injury increases the hope of attenuating secondary damage and maximizing an improved outcome.

Methylprednisolone sodium succinate (MPSS) plus rhEPO started within 6 hours after acute spinal injury may be more effective than MPSS plus placebo in improvement of neurologic dysfunction. More studies with larger sample sizes are warranted 3).

A study was designed to deliver the erythropoietin (EPO) into the N-methyl-N-nitrosourea (MNU) induced mice, a pharmacological retinopathy model via intranasal or intravenous route. The mice were then subjected to bioavailability assay and therapeutic effects evaluation.

The results showed that the intranasal delivery of EPO is effective to alleviate the morphological disruptions in the MNU induced mice. The intranasal delivery of EPO also ameliorated the visual impairments in the MNU induced mice. Immunostaining experiment showed that both the M-cone and S-cone populations in the degenerative retinas are rescued by the intranasal delivery of EPO. In particular, the M-cone photoreceptors in dorsal-temporal (DT) quadrant and the S-cone photoreceptors in ventral-nasal (VN) quadrant were preferentially preserved by the intranasal delivery of EPO. Mechanism studies showed that the intranasal delivery of EPO could the modulate apoptosis and restrict oxidation in the degenerative retina. Compared with intravenous delivery, the intranasal delivery led to the significantly higher EPO concentration in the retina. The intranasal delivery resulted in more potent protection and had less erythropoiesis-stimulating activity than the intravenous delivery. Our results suggest that the intranasal administration is a noninvasive and efficient approach to deliver EPO into the retinas. These findings lay the groundwork for further intranasal administration of EPO in ophthalmological practice 4).


A 42-year-old female patient presented with gait instability and progressive weakness in her right leg over a 6-year period. She was diagnosed as myelomalacia and was candidate for cervical discectomy. After surgery, she suffered from right hemiplegia due to spinal cord injury that did not respond well to routine treatment. Darbepoetin alpha (Aranesp) 100 mcg, subcutaneous daily for three days, was added to the patient's treatment seven days after trauma and resulted in rapid improvement. The patient recovered progressively and was discharged from the hospital ten days after erythropoietin therapy.

This case report supports the beneficial role of erythropoietin in function, maintenance, and recovery of neurons. Erythropoietin is a double-edge sword, as long-term erythropoietin therapy has some complications, like thromboembolism and stroke. Recent studies suggested that erythropoietin should be given as single high dose to exert a rapid neuro-protective effect with minimal hematopoietic side effects. The authors believe that the effects and other adverse consequences of erythropoietin and its non-erythropoietic derivatives should be evaluated in clinical trials 5).

Robinson S, Winer JL, Kitase Y, Brigman JL, Jantzie LL. Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency. J Neurosci Res. 2021 Feb 20. doi: 10.1002/jnr.24815. Epub ahead of print. PMID: 33611820.
Tang Z, Yang G, Wang X, et al. AKT/GSK-3β/beta-catenin signaling pathway participates in erythropoietin-promoted glioma proliferation [published online ahead of print, 2020 Sep 9]. J Neurooncol. 2020;10.1007/s11060-020-03602-9. doi:10.1007/s11060-020-03602-9
Alibai E, Zand F, Rahimi A, Rezaianzadeh A. Erythropoietin plus Methylprednisolone or Methylprednisolone in the Treatment of Acute Spinal Cord Injury: a Preliminary Report. Acta Med Iran. 2014 Apr;52(4):275-279. PubMed PMID: 24901857.
Tao Y, Li C, Yao A, Qu Y, Qin L, Xiong Z, Zhang J, Wang W. Intranasal administration of erythropoietin rescues the photoreceptors in degenerative retina: a noninvasive method to deliver drugs to the eye. Drug Deliv. 2019 Dec;26(1):78-88. doi: 10.1080/10717544.2018.1556361. PubMed PMID: 30744451; PubMed Central PMCID: PMC6374977.
Nekoui A, Del Carmen Escalante Tresierra V, Abdolmohammadi S, Shedid D, Blaise G. Neuroprotective Effect of Erythropoietin in Postoperation Cervical Spinal Cord Injury: Case Report and Review. Anesth Pain Med. 2015 Nov 28;5(6):e28849. doi: 10.5812/aapm.28849. eCollection 2015 Dec. PubMed PMID: 26705520.
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