The Recombinant Human Erythropoietin Administered in Neonatal Rats After Excitotoxic Damage Induces Molecular Changes in the Hippocampus

Abstract

In vitro and in vivo experimental evidence has contributed important knowledge regarding the antiapoptotic effect mediated by EPO signaling in the damaged brain, particularly through different models with a hypoxic component. However, little emphasis has been placed on the effectiveness of rhEPO administration against cellular alterations caused by in vivo excitotoxicity or on the molecular mechanism that regulates this effect. In this study, we investigated the effects of a single dose of rhEPO on hippocampal damage induced by subcutaneous application of monosodium glutamate (MSG) on postnatal days 1, 3, 5 and 7 in neonatal rats. We found that a dose of 1000 IU/kg of b.w. administered 24 h after MSG had the greatest protective effect. In addition, we analyzed changes in gene expression, particularly in 3 key molecules involved in EPO-mediated signaling (EPO, EPOR and βcR). We observed that the expression of EPO and EPOR was differentially modified at both the mRNA and protein levels under the evaluated conditions, while the expression of the βcR gene was substantially increased. Our data suggest that a low dose of rhEPO is sufficient to induce cellular protection under these experimental conditions and that the molecular changes could be a positive feedback mechanism, mediated by reactive astrocytes in association with in vivo neuroprotective mechanisms.

Beneficial Effect of Erythropoietin on Ameliorating Propionic Acid-Induced Autistic-Like Features in Young Rats

“…These findings were supported by silver staining, which showed few distorted, faintly stained PCs among apparently normal cells with regular nerve fibers in the molecular layer, in addition to the preserved ultrastructural features of PCs, the significant increase in the mean number of apparently normal PCs, calbindin expression in PCs, and a significant decrease in astrogliosis compared to PPA-Gp. Rivera-Cervantes et al ., 2019 [ 27 ] reported that treatment with EPO was associated with an increase in the number of normal cells with no observed cellular abnormalities in the brain, and no statistically significant differences were found regarding the control group. In a rat model of bile duct ligation-induced neuroinflammation, gliosis and neurodegeneration were significantly decreased by EPO administration [ 16 ].…”

Renoprotective effect of carbamylated darbepoetin and udenafil in ischemia-reperfusion of rat kidney due to the effect of preconditioning and inhibition of nuclear factor kappa B

“…EPO exerts its hematopoietic properties through its connection with the homodimeric erythropoietin receptor (EPOR) on the precursors of the erythroid lineage in the bone marrow, accelerating the processes of erythropoiesis and increasing the number of mature erythrocytes (Watowich 2011, Kuhrt and Wojchowski 2015, Bhoopalan et al 2020. However, there is also a heterodimeric erythropoietin complex EPOR/ βCR, which consists of EPOR in combination with the ubiquitous β-common receptor (Brines et al 2004, Rivera-Cervantes et al 2019, Vázquez-Méndez et al 2020. Implementation of the cytoprotective properties of EPO in various models of ischemia-reperfusion is associated primarily with the activation of signaling cascades triggered by a short contact of erythropoietin with this receptor complex Cerami 2008, Collino et al 2015).…”

Recombinant Erythropoietin Provides Protection against Renal Fibrosis in Adenine-Induced Chronic Kidney Disease

“…Recent studies have shown that supratherapeutic doses of rEPO can exert cytoprotective effects in some tissues, kidney tissue included, by activating the heterodimer formed by the interleucine-3 β common receptor (βcR) and the EPOR [7][8][9]. There is evidence that EPO derivatives can ameliorate kidney cell damage by upregulating nitric oxide production and strengthening antiapoptotic processes [7,10,11] as well as by downregulating the transdifferentiation of epithelial and endothelial cells into activated myofibroblasts that contribute to excessive extracellular matrix formation and ultimately tubulointersticial fibrosis [12,13].…”