Targeting erythropoietin for chronic neurodegenerative diseases

Chong, Zhao Zhong; Shang, Yan; Mu, Yifen; Cui, Shu‐Xiang; Yao, Qingqiang; Maiese, Kenneth

doi:10.1517/14728222.2013.780599

Cited by 23 publications

(22 citation statements)

References 129 publications

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“…EPO modulates various signaling pathways and transcription factors and may use these mechanisms to regulate miRNA expression (8). Another interesting point is the differences between EPO and its variant carbamylated EPO (42).…”

Section: Discussionmentioning

confidence: 99%

“…EPO’s impact on regulation at both the transcriptional and the post-transcriptional levels may play a critical role for its cellular effects. EPO activates various signaling pathways that result in gene expression changes responsible for its biological activities (8). Previous in vitro (9) and in vivo (10–14) studies using mRNA microarrays evaluated genome-wide expression changes induced by EPO.…”

Section: Introductionmentioning

confidence: 99%

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EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells

et al. 2014

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Erythropoietin (EPO) is a neuroprotective cytokine, which has been applied in several animal models presenting neurological disorders. One of the proposed modes of action resulting in neuroprotection is post-transcriptional gene expression regulation. This directly brings to mind microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression at the post-transcriptional level. It has not yet been evaluated whether miRNAs participate in the biological effects of EPO or whether it, inversely, modulates specific miRNAs in neuronal cells. In this study, we employed miRNA and mRNA arrays to identify how EPO exerts its biological function. Notably, miR-451 and miR-885-5p are downregulated in EPO-treated SH-SY5Y neuronal-like cells. Accordingly, target prediction and transcriptome analysis of cells treated with EPO revealed an alteration of the expression of genes involved in apoptosis, cell survival, proliferation, and migration. Low expression of miRNAs in SH-SY5Y was correlated with high expression of their target genes, vascular endothelial growth factor A, matrix metallo peptidase 9 (MMP9), cyclin-dependent kinase 2 (CDK2), erythropoietin receptor, Mini chromosome maintenance complex 5 (MCM5), B-cell lymphoma 2 (BCL2), and Galanin (GAL). Cell viability, apoptosis, proliferation, and migration assays were carried out for functional analysis after transfection with miRNA mimics, which inhibited some biological actions of EPO such as neuroprotection, anti-oxidation, anti-apoptosis, and migratory effects. In this study, we report for the first time that EPO downregulates the expression of miRNAs (miR-451 and miR-885-5p) in SH-SY5Y neuronal-like cells. The correlation between the over-expression of miRNAs and the decrease in EPO-mediated biological effects suggests that miR-451 and miR-885-5p may play a key role in the mediation of biological function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells

et al. 2014

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“…Under normal conditions, the Epo receptor (EpoR) is mainly expressed by neurons [ 22 ] but during insults such as hypoxia, ischemia, and trauma all cells including neurons, microglia, and astrocytes [ 19 , 23 , 24 ] are able to upregulate the Epo signaling cascade eliciting both autocrine and paracrine effects [ 18 ]. Although the exact mechanisms behind Epo’s neuroprotective effects are not well understood, its putative anti-inflammatory actions and enhancement of survival signals probably play a key role [ 7 , 25 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

Moransard

Bednar

Frei

et al. 2017

J Neuroinflammation

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BackgroundTreatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo’s beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both?MethodsTo address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival.ResultsAlthough disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons.ConclusionsOur data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0976-5) contains supplementary material, which is available to authorized users.

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“…The hematopoietic cytokine erythropoietin (EPO) acts as a cytoprotective agent in both neuronal and vascular systems which make it a candidate drug for neuroprotection [ 16 ]. Similar to BDNF, EPO is considered to have applicability in a variety of neuropsychiatric disorders [ 17 ] and it is capable of modulating multiple cellular signal transduction pathways to promote neuronal survival and enhance proliferation and differentiation of neuronal cells [ 18 ]. EPO crosses the blood-brain barrier [ 19 ] and is a potent growth factor that can protect CNS cells against apoptosis and promote proliferation of neuronal cells [ 18 ], thereby potentially being capable of preventing the progression of neurodegenerative processes in mood episodes.…”

Section: Introductionmentioning

confidence: 99%

“…Similar to BDNF, EPO is considered to have applicability in a variety of neuropsychiatric disorders [ 17 ] and it is capable of modulating multiple cellular signal transduction pathways to promote neuronal survival and enhance proliferation and differentiation of neuronal cells [ 18 ]. EPO crosses the blood-brain barrier [ 19 ] and is a potent growth factor that can protect CNS cells against apoptosis and promote proliferation of neuronal cells [ 18 ], thereby potentially being capable of preventing the progression of neurodegenerative processes in mood episodes. Evidence from preclinical studies, human neuroimaging studies, and recent clinical trials provide some indication for antidepressive cognitive enhancement effect, which might be mediated by action on EPO receptors located in the CNS [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Recombinant Erythropoietin on Plasma Brain Derived Neurotrophic Factor Levels in Patients with Affective Disorders: A Randomised Controlled Study

et al. 2015

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The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) ≤ 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU) or saline (0.9% NaCl) infusions in a double-blind, placebo-controlled, parallel—group design. Plasma BDNF levels were measured at baseline and at weeks 5, 9 and at follow up, week 14. In contrast with our hypothesis, EPO down regulated plasma BDNF levels in patients with TRD (mean reduction at week 9 (95% CI): EPO 10.94 ng/l (4.51-21.41 ng/l); mean increase at week 9: Saline 0.52 ng/l, p=0.04 (-5.88-4.48 ng/l) p=0.04, partial ŋ2=0.12). No significant effects were found on BDNF levels in partially remitted patients with BD (p=0.35). The present effects of EPO on BDNF levels in patients with TRD point to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers.Trial RegistrationClinicalTrials.gov: NCT00916552.

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Targeting erythropoietin for chronic neurodegenerative diseases

Cited by 23 publications

References 129 publications

EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells

EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells

Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

The Effect of Recombinant Erythropoietin on Plasma Brain Derived Neurotrophic Factor Levels in Patients with Affective Disorders: A Randomised Controlled Study

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