Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus

Sathyanesan, Monica; Watt, Michael J.; Haiar, Jacob; Scholl, Jamie L.; Davies, Shaydel R; Paulsen, Riley T.; Wiederin, Jayme; Ciborowski, Paweł; Newton, Samuel S.

doi:10.1038/s41398-018-0168-9

Cited by 22 publications

(31 citation statements)

References 55 publications

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“…The apparent lack of hematopoietic cascade activation raises interesting questions regarding CEPO's mechanisms of action in mediating behavioral effects which are comparable to EPO (6,16). Gene expression studies have shown that EPO (16) and CEPO (11) share an overlap in the neurotrophic factors that they induce in the hippocampus, such as BDNF, VGF and neuritin. These three neurotrophic molecules have been previously shown to independently produce antidepressant-like and cognitive enhancing effects in rodent models (17)(18)(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

“…Erythropoietin was purchased from Prospec Bio (Israel) and carbamoylated in 1 mg aliquots as previously reported (5,11). Briefly, EPO was deprotonated in a high pH (pH = 8.9) borate buffer and then exposed to potassium cyanate for 16hr at 36 °C.…”

Section: Materials and Methods: Carbamoylation Of Epomentioning

confidence: 99%

“…Rats received single daily i.p. injections of either vehicle (PBS), EPO or CEPO (30 µg/kg) for 4 consecutive days (5,11). Five hours after the last dose animals were decapitated according to American Veterinary Medical Association guidelines.…”

Section: Animalsmentioning

confidence: 99%

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A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles

Tiwari

Sathyanesan

Kumar

et al. 2020

Preprint

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In recent years erythropoietin (EPO) has emerged as a useful neuroprotective and neurotrophic molecule that produces antidepressant and cognitive enhancing effects in psychiatric disorders.However, EPO robustly induces erythropoiesis and elevates red blood cell counts. Chronic administration is therefore likely to increase blood viscosity and produce adverse effects in nonanemic populations. Carbamyolated erythropoietin (CEPO), a chemically engineered modification of EPO, is non-erythropoietic but retains the neurotrophic and neurotrophic activity of EPO. Blood profile analysis after EPO and CEPO administration showed that CEPO has no effect on red blood cell or platelet counts. We conducted an unbiased, quantitative, mass spectrometry-based proteomics study to comparatively investigate EPO and CEPO-induced protein profiles in neuronal phenotype PC12 cells. Bioinformatics enrichment analysis of the protein expression profiles revealed the upregulation of protein functions related to memory formation such as synaptic plasticity, long term potentiation (LTP), neurotransmitter transport, synaptic vesicle priming, and dendritic spine development. The regulated proteins, with roles in LTP and synaptic plasticity, include Neudesin, Chromogranin b, Cortactin, Elongation initiation factor 3a and Proteasome 26s subunit, ATPase. We examined the expression of a subset of regulated proteins by immunohistochemical analysis in mouse brain. The results of our study sheds light on potential mechanisms whereby EPO and CEPO produce cognitive enhancing effects in clinical and preclinical studies. Introduction:Erythropoietin (EPO) is a 165 amino acid glycoprotein with well-known roles in red blood cell production in the body. Besides erythropoiesis, EPO also acts as an important neurotrophic molecule in brain development. After brain injury, the levels of EPO have been shown to increase in the brain, where it functions as a neuroprotectant (1). Due to its neurotrophic and neuroprotective effects, EPO has been extensively tested in both preclinical and clinical CNS studies. Treatment-resistant depressed patients treated with EPO in a double-blind, randomized clinical trial reported improvement in depression scores and cognition (2). EPO clinical trials conducted in combination with brain imaging reported a positive correlation between memory improvement and reversal of brain matter loss in

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Section: Discussionmentioning

confidence: 99%

Section: Materials and Methods: Carbamoylation Of Epomentioning

confidence: 99%

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A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles

Tiwari

Sathyanesan

Kumar

et al. 2020

Preprint

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“…CEPO was produced as per our CEPO characterization study. 13 RNA Isolation, cDNA Synthesis, and RT-qPCR RNA isolation was carried out using an Invitrogen RNAqueous Phenol-Free Total RNA Isolation Kit (AM-1912) following the manufacturer's instructions.…”

Section: Ngepo and Cepomentioning

confidence: 99%

“…11 The existence of the IRR is supported by the binding affinity measurements of EPO's carbamoylated form (CEPO), 12 in which we found that seven surface lysine residues were carbamoylated. 13 CEPO loses the ability to activate the classical EPOR/EPOR homodimer conformation and has no hematopoietic activity in-vivo or invitro. 12 However, CEPO retains EPO's neuroactive affects, implying that not only is EPOR/EPOR not mediating these effects but also that CEPO is a selective agonist of the IRR.…”

Section: Introductionmentioning

confidence: 99%

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Pekas¹,

Petersen²,

Sathyanesan³

et al. 2020

DDDT

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Introduction: Carbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and procognitive effects, which are attributed to the increased expression of neurotrophic factors like brain derived neurotrophic factor (BDNF), in the central nervous system. However, the chemical modification process which produces CEPO from erythropoietin (EPO) requires pure EPO as raw material, is challenging to scale-up and can also cause batch-to-batch variability. To address these key limitations while retaining its behavioral effects, we designed, expressed and analyzed a triple, glutamine, substitution recombinant mimetic of CEPO, named QPO. Methods and Materials: We employ a combination of computational structural biology, molecular, cellular and behavioral assays to design, produce, purify and test QPO. Results: QPO was shown to be a nonhematopoietic polypeptide with significant antidepressant-like and pro-cognitive behavioral effects in rodent assays while significantly upregulating BDNF expression in-vitro and in-vivo. The in-silico binding affinity analysis of QPO bound to the EPOR/EPOR homodimer receptor shows significantly decreased binding to Active Site 2, but not Active Site 1, of EPOR. Discussion: The results of the behavioral and gene expression analysis imply that QPO is a successful CEPO mimetic protein and potentially acts via a similar neurotrophic mechanism, making it a drug development target for psychiatric disorders. The decreased binding to Active Site 2 could imply that this active site is not involved in neuroactive signaling and could allow the development of a functional innate repair receptor (IRR) model. Substituting the three glutamine substitution residues with arginine (RPO) resulted in the loss of behavioral activity, indicating the importance of glutamine residues at those positions.

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Iron, neuro‐bioavailability and depression

Berthou

Iliou²,

Barba³

2021

eJHaem

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Medical management of iron deficiency (ID) requires to consider its consequences in biochemical and physiological plural functions, beyond heme/hemoglobin disrupted synthesis. Fatigue, muscle weakness, reduced exercise capacity, changes in thymia and modified emotional behaviors are the commonest symptoms integrated in the history of ID, dependent or not of the hemoglobin concentration. The relationship between depression and absolute ID (AID) is a condition which is often unrecognized. Neuro‐bioavailability and brain capture of blood iron are necessary for an appropriate synthesis of neurotransmitters (serotonin, dopamine, noradrenaline). These neurotransmitters, involved in emotional behaviors, depend on neuron aromatic hydoxylases functioning with iron as essential cofactor. Noradrenaline also has impact on neuroplasticity via brain‐derived neurotrophic factor (BDNF), which is key for prefrontal and hippocampus neurons playing a role in depression. Establishing the formal relationship between depression and AID remains difficult. Intracerebral reduced iron is still hard to quantify by neuroimaging and single‐photon emission computed tomography (SPECT) now tends to explore the neurotransmission pathways. AID has to be looked for and identified in the context of depression, major episode or resistant to conventional treatment such as serotonin reuptake inhibitor, and even in the absence of anemia, microcytosis or hypochromia (non‐anemic ID). Confronted to brain imaging, blood iron status evaluation is indicated, especially in depressed, treatment‐resistant, iron‐deficient young women. In patients suffering from depression, increase in the prevalence of AID should be considered, in order to deliver a suitable treatment, considering both anti‐depressive program and iron supplementation if AID.

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Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus

Cited by 22 publications

References 55 publications

A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles

A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Iron, neuro‐bioavailability and depression

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