Neuroprotective effects of erythropoietin
on Alzheimer’s dementia model in rats

Çevik, Betül; Solmaz, Volkan; Yiğittürk, Gürkan; Çavuşoğlu, Türker; Peker, Gonul; Erbaş, Oytun

doi:10.17219/acem/61044

Cited by 33 publications

(24 citation statements)

References 26 publications

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“…EPO binds to EPO receptors (EPOR) on the surface of the erythroid progenitor cells to stimulate erythropoiesis in the bone marrow [18,19] and is clinically used to treat anemia [20,21]. Besides its role in erythropoiesis, EPO is a neurotrophin and offers therapeutic benefits in mouse models of neural diseases [22], and in the past decade, numerous studies have reported the protective effects of chronic rhu‐EPO dosing in experimental AD [23–28]. Given the role of EPO in proliferation and differentiation of erythroid progenitor cells, hematopoietic side effects are the major concern associated with chronic rhu‐EPO use; however, only a small number of studies report the hematopoietic effects of chronic rhu‐EPO use in experimental AD [24].…”

Section: Discussionmentioning

confidence: 99%

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Sun

Yang

Whitman

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Low blood‐brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor‐mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB‐penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb‐EPO dosing, in comparison to recombinant human EPO (rhu‐EPO), in AD mice. Methods Male APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb‐EPO (3 mg/kg, n = 7), or rhu‐EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline‐treated wild‐type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aβ) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential. Results cTfRMAb‐EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu‐EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu‐EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1‐rhu‐EPO mice. Both cTfRMAb‐EPO and rhu‐EPO decreased 6E10‐positive brain Aβ load; however, cTfRMAb‐EPO and not rhu‐EPO selectively reduced brain Aβ1‐42 and elevated synaptophysin expression. Discussion Chronic treatment with cTfRMAb‐EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu‐EPO, supporting the development of this BBB‐penetrable EPO analog for AD.

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Section: Discussionmentioning

confidence: 99%

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Sun

Yang

Whitman

et al. 2019

A&D Transl Res & Clin Interv

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“…EPO and its receptors are found in the CNS of mammals, and are essential for neurodevelopment, adult neurogenesis, and neuroprotection. In animal models of neurodegenerative diseases including AD, neuroprotective and neuroregenerative mechanisms of EPO are related to inhibiting apoptosis, reducing oxidative stress and inflammation, promoting the angiogenesis and neurogenesis, and maintaining blood brain barrier (BBB) integrity [ 31 ]. The latter effect might be especially important mechanism in OXYS model due to neurovascular disturbances registered in OXYS rats [ 10 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties

et al. 2018

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Background The dominant hypothesis about the pathogenesis of Alzheimer’s disease (AD) is the “amyloid cascade” concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD. The molecular mechanisms of this effect are not completely clear, we suggested that the drug might serve as the regulator of the expression of the genes involved in the metabolism of Aβ and the pathogenesis of AD. The study was aimed to determine the effects of CEF on mRNA levels of Bace1 (encoding β-secretase BACE1 involved in Aβ production), Mme, Ide, Ece1, Ace2 (encoding enzymes involved in Aβ degradation), Epo (encoding erythropoietin related to endothelial function and clearance of Aβ across the blood brain barrier) in the frontal cortex, hippocampus, striatum, hypothalamus, and amygdala of OXYS and Wistar (control strain) male rats. Starting from the age of 14 weeks, animals received CEF (100 mg/kg/day, i.p., 36 days) or saline. mRNA levels were evaluated with RT-qPCR method. Biochemical parameters of plasma were measured for control of system effects of the treatment.ResultsTo better understand strain variations studied here, we compared the gene expression between untreated OXYS and Wistar rats. This comparison showed a significant decrease in mRNA levels of Ace2 in the frontal cortex and hypothalamus, and of Actb in the amygdala of untreated OXYS rats. Analysis of potential effects of CEF revealed its novel targets. In the compound-treated OXYS cohort, CEF diminished mRNA levels of Bace1 and Ace2 in the hypothalamus, and Aktb in the frontal cortex. Furthermore, CEF augmented Mme, Ide, and Epo mRNA levels in the amygdala as well as the levels of Ece1 and Aktb in the striatum. Finally, CEF also attenuated the activity of ALT and AST in plasma of OXYS rats.ConclusionThose findings disclosed novel targets for CEF action that might be involved into neuroprotective mechanisms at early, pre-plaque stages of AD-like pathology development.

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“…Despite the idea that studies of adult neurogenesis in animal models of AD provided a great variability in results, which was dependent on experimental conditions, the age or promoter studied, and though neurogenesis was decreased and increased in its dependence of study conditions (reviewed in [140,141]), most strategies focused on the induction of neurogenesis. Adult neurogenesis can be stimulated through extrinsic administration of chemical agents and growth factors in the context of AD, such as: Erythropoietin [142,143,144], fluoxetine [145], granulocyte colony stimulating factor (G-CSF) and AMD3100 [146], brain-derived neurotrophic factor (BDNF) [147,148,149], insulin growth factor-1 (IGF-1) [150], nerve growth factor (NGF) [151,152], vascular endothelial growth factor (VEGF) [153], growth, and transforming growth factor β (TGF-β) [154]. In addition, neurogenesis becomes stimulated by voluntary running and physical exercise, as well as an enriched environment [155,156,157,158].…”

Section: Stem Cell Therapiesmentioning

confidence: 99%

Neurodegeneration and Neuro-Regeneration—Alzheimer’s Disease and Stem Cell Therapy

Vasić

Barth

Schmidt

2019

IJMS

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Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.

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Neuroprotective effects of erythropoietin on Alzheimer’s dementia model in rats

Abstract: Background. Although Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available.

Cited by 33 publications

References 26 publications

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties

Neurodegeneration and Neuro-Regeneration—Alzheimer’s Disease and Stem Cell Therapy

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