Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases

Abstract

Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both in vitro and in vivo, characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.

Keywords: erythropoietin; neurodegeneration; neuroinflammation; neuroprotection.

Figure 1.

Different isoforms of EPOR in the CNS. In its canonical isoform, EPO’s binding leads to the homodimerization of the receptor and phosphorylation of JAK2 molecules. This activates specific intracellular pathways (STAT-PI3K-MAPK). In the second case, the EPOR monomer interacts with the beta common receptor βcR activating the JAK2 pathway. A third isoform of the receptor occurs in dopaminergic neurons of the substantia nigra, where EPOR results altered in the extra regional domain. In this case, the isoform is shorter than the full form, leading to the lack of STAT phosphorylation. Last, a soluble version of the receptor has been found in the murine brain. This isoform interacts with EPO, with no activation of any downstream pathway. This leads to a reduced availability of EPO, thereby reducing its interaction with other isoforms of EPOR. Made in ©BioRender—biorender.com aa = amino acids; EPOR = erythropoietin receptor; JAK2 = Janus tyrosine kinase 2; MAPK = mitogen-activated protein kinase; PI3K = phosphatidylinositol 3-kinase; STAT = signal transducer and activator of transcription.

Figure 2.

Neurotrophic role of EPO’s binding with EPOR. In the CNS, EPO’s binding to its receptor leads to an increase in neuroprotective actions (synaptic plasticity, neurogenesis, autophagy) with an overall functional recovery in animal models. Conversely, the binding leads to a decrease in apoptosis, expression of miRNAs regulating the apoptotic process, oxidative stress, and neuroinflammation. Made in ©BioRender—biorender.com EPO = erythropoietin; EPOR = erythropoietin receptor.

Figure 3.

Role of the EPO/EPOR pathway in opposing the oxidative stress induced by hypoxia or hyperoxia. Both hypoxia and hyperoxia are sources of oxidative stress and activate the HIF pathway, which leads to increased EPO expression and EPO/EPOR interaction, which activates the antiapoptotic STAT3 pathway, and increases the antioxidant enzymes expression through the Nrf1 pathway. Green arrows: activation. Red lines: inhibition. Made in ©BioRender—biorender.com EPO = erythropoietin; EPOR = erythropoietin receptor; HIF-1 = hypoxia-inducible factor 1; IL-6 = interleukin-6; IL-8 = interleukin-8; Nrf1 = nuclear respiratory factor 1; TNF-α = tumor necrosis factor alpha; ROS = reactive oxygen species; STAT3 = signal transducer and activator of transcription 3.