Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer’s Disease

Abstract

Substantial evidence in the literature demonstrates the pleiotropic effects of the administration of recombinant human erythropoietin (rhEPO) and its molecular variants in different tissues and organs, including the brain. Some of these reports suggest that the chemical properties of this molecule by itself or in combination with other agents (e.g., growth factors) could provide the necessary pharmacological characteristics to be considered a potential protective agent in neurological disorders such as Alzheimer’s disease (AD). AD is a degenerative disorder of the brain, characterized by an aberrant accumulation of amyloid β (Aβ) and hyperphosphorylated tau (tau-p) proteins in the extracellular and intracellular space, respectively, leading to inflammation, oxidative stress, excitotoxicity, and other neuronal alterations that compromise cell viability, causing neurodegeneration in the hippocampus and the cerebral cortex. Unfortunately, to date, it lacks an effective therapeutic strategy for its treatment. Therefore, in this review, we analyze the evidence regarding the effects of exogenous EPOs (rhEPO and its molecular variants) in several in vivo and in vitro Aβ and tau-p models of AD-type neurodegeneration, to be considered as an alternative protective treatment to this condition. Particularly, we focus on analyzing the differential effect of molecular variants of rhEPO when changes in doses, route of administration, duration of treatment or application times, are evaluated for the improved cellular alterations generated in this disease. This narrative review shows the evidence of the effectiveness of the exogenous EPOs as potential therapeutic molecules, focused on the mechanisms that establish cellular damage and clinical manifestation in the AD.

Beta-Sitosterol Promotes Milk Protein and Fat Syntheses-Related Genes in Bovine Mammary Epithelial Cells

“…Notably, it regulates a series of hypoxia signal pathways to enhance the expression of erythropoietin (EPO) and its receptor (erythropoietin receptor, EPOR) genes [ 44 ], thereby promoting the proliferation and differentiation of mammalian erythroid progenitor cells. Studies also postulate that EPO has anti-inflammatory, antiapoptotic, neuroprotective, and other non-erythropoietic effects [ 45 ]. Its function depends on the EPO-EPOR signal transduction mechanism [ 46 , 47 ], which induces downstream factors, such as the PI3K/AKT pathway, for further activation.…”

The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review

“…These actions allow for cell survival, proliferation, and differentiation. Activation of the homodimeric EPOR/EPOR leads to erythropoiesis, while activation of the heterodimeric EPOR/βcR (CD131) leads to tissue repair and recovery ( Socolovsky et al, 2001 ; Tsiftsoglou, 2021 ; Maiese, 2015 ; Gyetvai et al, 2017 ; Othman et al, 2018 ; Jarero-Basulto et al, 2020 ; Peng et al, 2020 ; Jacobs et al, 2021 ; Larpthaveesarp et al, 2021 ). The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is involved in many vital cellular processes, including cell growth, differentiation, proliferation, and regulatory immune functions; PI3K/AKT (Phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B) is activated by numerous genes and improves cell proliferation during erythropoiesis in hypoxia; ERK/MAPK (extracellular signal-regulated kinase/Mitogen-activated protein kinase) is the key signaling pathway that regulates a wide variety of cellular processes, including proliferation, differentiation, apoptosis, and stress responses; GATA1, FOG1, TAL-1, and EKLF (Erythroid Kruppel-like Factor, also called KLF1) are master transcriptional regulators of erythropoiesis; BC11A, transcriptional repressor B-cell lymphoma/leukemia 11A, is a transcriptional repressor of erythropoiesis; TGF-β, transforming growth factor-β, regulates cell growth and differentiation, apoptosis, etc.…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…EPO is then processed with the removal of a carboxy-terminal arginine 166 in the mature human and recombinant human EPO (rhEPO). A protein of 165 amino acids with a molecular weight of 30.4 kDa is subsequently generated [231][232][233][234]. EPO expression is present in the brain, uterus, and liver, but the primary site for the production and secretion of EPO is the kidney peritubular interstitial cells [229,230,[235][236][237][238].…”