Erythropoietin and derivatives: Potential beneficial effects on the brain

Abstract

Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on nonhematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression.Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated.Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

“…Erythropoietin (Epo) is an erythropoiesis-stimulating hormone which is also endowed of cytoprotective effects in non-hematopoietic tissues, including the brain. By binding to its receptors, which are largely expressed in the CNS, Epo exerts its neuroprotective properties by activating antioxidant and anti-inflammatory signaling pathways, which stimulate neurogenesis and lead to a downstream reduction of neuronal apoptosis [ 131 ]. In vitro studies investigating Epo-related antioxidant effects on the brain tissue have shown a suppressed ROS production in microglial cells [ 132 ], restoration of GP activity in substantia nigra and astroglial cells [ 133 ], reduced brain levels of lipid peroxidation products [ 134 ] and of NO [ 135 ] following Epo administration.…”

Erythropoietin Interacts with Specific S100 Proteins

“…Erythropoietin (EPO) is a pleiotropic monomeric glycosylated short-chain four-helical cytokine (SCOP entry 4000852; newly synthesized EPO is the 193-residue long protein containing a 27-residue long signal peptide, which is removed upon maturation, giving rise to 166 residues in mature form, 30.4 kDa), mainly produced by adult kidney type I interstitial cells, fetal liver hepatocytes, and Ito cells [ 1 , 2 , 3 , 4 , 5 ]. EPO signals through homodimer of the EPO receptor (EPOR), the heterodimer of the EPOR and the β common receptor (CD131, βcR) or the Ephrin type-B receptor 4 (EphB4) [ 6 , 7 , 8 , 9 ].…”

“…The global EPO drugs market size has already reached 12 billion USD and is estimated to grow at a compound annual growth rate (CAGR) of 10%, according to the Market Data Forecast. Other EPO-based therapeutic applications are under development, including prevention of dementia, Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, depression, ischemic stroke, traumatic brain injury, diabetes mellitus, acute and chronic lung diseases, various ocular diseases, severe COVID-19, as well as EPO use in the regenerative medicine [ 1 , 3 , 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. However, the clinical use of the EPO-based medicines is limited due to the pleiotropic nature of this cytokine, leading to serious adverse reactions, such as arterial hypertension, cerebral convulsion/hypertensive encephalopathy, thrombo-embolism, iron deficiency, development of pure red cell aplasia, and the possibility of cancer progression [ 8 , 22 , 23 ].…”

Effect of intranasal administration of neuroEPO in the histological structure of the olfactory mucosa of rats Wistar

“…In recent decades, intense research has been carried out in the search for new therapies to treat neurological diseases. Different variants of erythropoietin (EPO) have been evaluated for the treatment of neurological diseases reporting satisfactory and encouraging results (4,5).…”