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Erythropoietin

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 24108

Special Issue Editors

Prof. Dr. Robin K. Ohls

E-Mail Website
Guest Editor
Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA
Interests: erythropoiesis; fetal gene expression; neuroprotection; neonatal anemia and transfusions; neurodevelopmental outcomes of preterm infants
Dr. Lauren L. Jantzie

E-Mail Website
Guest Editor
Division of Neonatal-Perinatal Medicine, Department of Pediatrics and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Interests: perinatal brain injury; chorioamnionitis; posthemorrhagic hydrocephalus; pediatric traumatic brain injury; neuroinflammation; cerebral hypoxia-ischemia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Erythropoiesis-stimulating agents (ESAs) such as erythropoietin (Epo) and Darbepoetin (Darbe) have been used for over 30 years as red cell growth factors in adults, children, and infants with anemia due to a variety of conditions. Recently, studies have focused on the potential neuroprotective effects of ESAs. Neuroprotective and neuroreparative mechanisms evaluated include decreased apoptosis, increased oligodendrogenesis and neurogenesis, and neuronal protection against inflammation and oxidative injury. This Special Issue of the International Journal of Molecular Sciences will focus on the study and review of hematopoietic and neuroprotective mechanisms of erythropoietin and newer long-acting erythropoiesis-stimulating agents. Therapeutic uses in a variety of populations will be explored.

Prof. Dr. Robin K. Ohls
Dr. Lauren L. Jantzie
Guest Editors

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Keywords

  • erythropoietin
  • anemia
  • transfusion
  • erythropoiesis
  • neurodevelopment
  • neurorepair
  • neurorestoration
  • neurogenesis
  • oligodendrogenesis
  • perinatal brain injury

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Published Papers (4 papers)

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Research

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11 pages, 2494 KiB  
Article
Erythropoietin Mediated Bone Loss in Mice Is Dose-Dependent and Mostly Irreversible
by Albert Kolomansky, Sahar Hiram-Bab, Nathalie Ben-Califa, Tamar Liron, Naamit Deshet-Unger, Moshe Mittelman, Howard S. Oster, Martina Rauner, Ben Wielockx, Drorit Neumann and Yankel Gabet
Int. J. Mol. Sci. 2020, 21(11), 3817; https://doi.org/10.3390/ijms21113817 - 27 May 2020
Cited by 10 | Viewed by 3430
Abstract
Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led [...] Read more.
Recent studies have demonstrated that erythropoietin (EPO) treatment in mice results in trabecular bone loss. Here, we investigated the dose-response relationship between EPO, hemoglobin (Hgb) and bone loss and examined the reversibility of EPO-induced damage. Increasing doses of EPO over two weeks led to a dose-dependent increase in Hgb in young female mice, accompanied by a disproportionate decrease in trabecular bone mass measured by micro-CT (µCT). Namely, increasing EPO from 24 to 540 IU/week produced a modest 12% rise in Hgb (20.2 ± 1.3 mg/dL vs 22.7 ± 1.3 mg/dL), while trabecular bone volume fraction (BV/TV) in the distal femur decreased dramatically (27 ± 8.5% vs 53 ± 10.2% bone loss). To explore the long-term skeletal effects of EPO, we treated mice for two weeks (540 IU/week) and monitored bone mass changes after treatment cessation. Six weeks post-treatment, there was only a partial recovery of the trabecular microarchitecture in the femur and vertebra. EPO-induced bone loss is therefore dose-dependent and mostly irreversible at doses that offer only a minor advantage in the treatment of anemia. Because patients requiring EPO therapy are often prone to osteoporosis, our data advocate for using the lowest effective EPO dose for the shortest period of time to decrease thromboembolic complications and minimize the adverse skeletal outcome. Full article
(This article belongs to the Special Issue Erythropoietin)
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20 pages, 10751 KiB  
Article
The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep
by Simerdeep K. Dhillon, Guido Wassink, Christopher A. Lear, Joanne O. Davidson, Nicholas H.G. Holford, Alistair J. Gunn and Laura Bennet
Int. J. Mol. Sci. 2020, 21(9), 3042; https://doi.org/10.3390/ijms21093042 - 25 Apr 2020
Cited by 6 | Viewed by 2951
Abstract
High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, [...] Read more.
High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO. Full article
(This article belongs to the Special Issue Erythropoietin)
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12 pages, 2507 KiB  
Article
Erythropoietin-Induced Changes in Bone and Bone Marrow in Mouse Models of Diet-Induced Obesity
by Sukanya Suresh, Josue Caban Alvarez, Soumyadeep Dey and Constance Tom Noguchi
Int. J. Mol. Sci. 2020, 21(5), 1657; https://doi.org/10.3390/ijms21051657 - 28 Feb 2020
Cited by 15 | Viewed by 4021
Abstract
Obesity remodels bone and increases bone marrow adipocytes (BMAT), which negatively regulate hematopoiesis and bone. Reduced BMAT could restore altered hematopoiesis and bone features. We analyzed the potential of erythropoietin (EPO), the cytokine required for erythropoiesis, to inhibit BMAT in C57BL6/J mice fed [...] Read more.
Obesity remodels bone and increases bone marrow adipocytes (BMAT), which negatively regulate hematopoiesis and bone. Reduced BMAT could restore altered hematopoiesis and bone features. We analyzed the potential of erythropoietin (EPO), the cytokine required for erythropoiesis, to inhibit BMAT in C57BL6/J mice fed four weeks of a high-fat diet (HFD). Acute EPO administration markedly decreased BMAT in regular chow diet (RCD) and HFD-fed mice, without affecting whole body fat mass. Micro-CT analysis showed EPO reduced trabecular bone in RCD- and HFD-fed mice, but EPO-treated HFD-fed mice maintained cortical bone mineral density and cortical bone volume, which was reduced on RCD. Despite achieving similar increased hematocrits with BMAT loss in RCD- and HFD-fed mice treated with EPO, decreased bone marrow cellularity was only observed in RCD-fed mice concomitant with an increasing percentage of bone marrow erythroid cells. In contrast, in HFD-fed mice, EPO increased endothelial cells and stromal progenitors with a trend toward the normalization of marrow homeostasis. EPO administration increased c-terminal FGF23 and intact serum FGF23 only in HFD-fed mice. These data demonstrate the distinct EPO responses of bone and marrow in normal and obese states, accompanying EPO-induced loss of BMAT. Full article
(This article belongs to the Special Issue Erythropoietin)
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Review

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27 pages, 1102 KiB  
Review
Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research
by Dorothy E. Oorschot, Rachel J. Sizemore and Ashraf R. Amer
Int. J. Mol. Sci. 2020, 21(4), 1487; https://doi.org/10.3390/ijms21041487 - 21 Feb 2020
Cited by 63 | Viewed by 13135
Abstract
Perinatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of morbidity and mortality. Moderate hypothermia (33.5 °C) is currently the sole established standard treatment. However, there are a large number of infants for whom this therapy is ineffective. This inspired global research to find [...] Read more.
Perinatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of morbidity and mortality. Moderate hypothermia (33.5 °C) is currently the sole established standard treatment. However, there are a large number of infants for whom this therapy is ineffective. This inspired global research to find neuroprotectants to potentiate the effect of moderate hypothermia. Here we examine erythropoietin (EPO) as a prominent candidate. Neonatal animal studies show that immediate, as well as delayed, treatment with EPO post-injury, can be neuroprotective and/or neurorestorative. The observed improvements of EPO therapy were generally not to the level of control uninjured animals, however. This suggested that combining EPO treatment with an adjunct therapeutic strategy should be researched. Treatment with EPO plus hypothermia led to less cerebral palsy in a non-human primate model of perinatal asphyxia, leading to clinical trials. A recent Phase II clinical trial on neonatal infants with HIE reported better 12-month motor outcomes for treatment with EPO plus hypothermia compared to hypothermia alone. Hence, the effectiveness of combined treatment with moderate hypothermia and EPO for neonatal HIE currently looks promising. The outcomes of two current clinical trials on neurological outcomes at 18–24 months-of-age, and at older ages, are now required. Further research on the optimal dose, onset, and duration of treatment with EPO, and critical consideration of the effect of injury severity and of gender, are also required. Full article
(This article belongs to the Special Issue Erythropoietin)
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