Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review

Li, Xian Bin; Zheng, Wei; Ning, Yu; Cai, Dong Bin; Yang, Xin; Ungvári, Gábor S.; Ng, Chee H.; Wang, Chuanyue; Xiang, Yu‐Tao

doi:10.1055/s-0043-114670

Cited by 21 publications

(10 citation statements)

References 37 publications

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“…In the last 20 years, erythropoietin (EPO) has emerged as a potential candidate for neuroprotective and neuroregenerative treatment in injury and disease of the nervous system (Sargin et al, 2010 ). Interestingly, EPO improves cognitive performance in healthy animals and humans and in disease, including in MS (Ehrenreich et al, 2007 ; Robinson et al, 2018 ; Li et al, 2018 ). Although the mechanism is still largely unknown, we and others showed that EPO acts directly on OLs to increase myelination in vitro and in vivo (Sugawa et al, 2002 ; Cervellini et al, 2013 ; Hassouna et al, 2016 ; Gyetvai et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

Gyetvai

Roe

Heikal

et al. 2018

Mol Med

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BackgroundThe pro-myelinating effects of leukemia inhibitory factor (LIF) and other cytokines of the gp130 family, including oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), have long been known, but controversial results have also been reported. We recently overexpressed erythropoietin receptor (EPOR) in rat central glia-4 (CG4) oligodendrocyte progenitor cells (OPCs) to study the mechanisms mediating the pro-myelinating effects of erythropoietin (EPO). In this study, we investigated the effect of co-treatment with EPO and LIF.MethodsGene expression in undifferentiated and differentiating CG4 cells in response to EPO and LIF was analysed by DNA microarrays and by RT-qPCR. Experiments were performed in biological replicates of N ≥ 4. Functional annotation and biological term enrichment was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene-gene interaction network was visualised using STRING (Search Tool for the Retrieval of Interacting Genes).ResultsIn CG4 cells treated with 10 ng/ml of EPO and 10 ng/ml of LIF, EPO-induced myelin oligodendrocyte glycoprotein (MOG) expression, measured at day 3 of differentiation, was inhibited ≥4-fold (N = 5, P < 0.001). Inhibition of EPO-induced MOG was also observed with OSM and CNTF. Analysis of the gene expression profile of CG4 differentiating cells treated for 20 h with EPO and LIF revealed LIF inhibition of EPO-induced genes involved in lipid transport and metabolism, previously identified as positive regulators of myelination in this system. In addition, among the genes induced by LIF, and not by differentiation or by EPO, the role of suppressor of cytokine signaling 3 (SOCS3) and toll like receptor 2 (TLR2) as negative regulators of myelination was further explored. LIF-induced SOCS3 was associated with MOG inhibition; Pam3, an agonist of TLR2, inhibited EPO-induced MOG expression, suggesting that TLR2 is functional and its activation decreases myelination.ConclusionsCytokines of the gp130 family may have negative effects on myelination, depending on the cytokine environment.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0052-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

Gyetvai

Roe

Heikal

et al. 2018

Mol Med

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“…Studies conducted in healthy and depressed individuals showed that, similar to the effects seen with conventional antidepressants, EPO reduces the neurocognitive processing of negative emotional information while concurrently improving cognitive function (Miskowiak et al, 2008(Miskowiak et al, , 2010. More recently, a meta-analysis determined that EPO alleviates the cognitive deficits associated with bipolar disorder, major depression, and schizophrenia without producing a significant unfavorable impact (Li et al, 2018). These beneficial effects of EPO are consistent with EPO's ability to regulate the activity of HPA axis (Tringali et al, 2007;Dey and Noguchi, 2017;Dey et al, 2020).…”

Section: Epo and The Regulation Of Stress And Respiratory Controlmentioning

confidence: 80%

Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

et al. 2021

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Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

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“…For instance, EPO appears to induce the production of brain-derived neurotrophic factor (BDNF) in the hippocampal tissue. In addition, in patients with schizophrenia, a decrease of S100 proteina marker for glial damagepredicted a better clinical outcome after one month of treatment [434,438,440,441]. Studies with mice receiving EPO showed an increase of LTP in the hippocampus.…”

Section: Erythropoietinmentioning

confidence: 98%

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

Bittner¹,

Barnes-Scheufler²,

Hettwer³

et al. 2021

Preprint

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Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

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Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review

Abstract: CRD42017058094.

Cited by 21 publications

References 37 publications

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes

Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

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