RESUMO
Memory and learning allow animals to appropriate certain properties of nature with which they can navigate in it successfully. Memory is acquired slowly and consists of two major phases, a fragile early phase (short-term memory, <4 h) and a more robust and long-lasting late one (long-term memory, >4 h). Erythropoietin (EPO) prolongs memory from 24 to 72 h when animals are trained for 5 min in a place recognition task but not when training lasted 3 min (short-term memory). It is not known whether it promotes the formation of remote memory (≥21 days). We address whether the systemic administration of EPO can convert a short-term memory into a long-term remote memory, and the neural plasticity mechanisms involved. We evaluated the effect of training duration (3 or 5 min) on the expression of endogenous EPO and its receptor to shed light on the role of EPO in coordinating mechanisms of neural plasticity using a single-trial spatial learning test. We administered EPO 10 min post-training and evaluated memory after 24 h, 96 h, 15 days, or 21 days. We also determined the effect of EPO administered 10 min after training on the expression of arc and bdnf during retrieval at 24 h and 21 days. Data show that learning induces EPO/EPOr expression increase linked to memory extent, exogenous EPO prolongs memory up to 21 days; and prefrontal cortex bdnf expression at 24 h and in the hippocampus at 21 days, whereas arc expression increases at 21 days in the hippocampus and prefrontal cortex.
Assuntos
Eritropoetina , Consolidação da Memória , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Eritropoetina/farmacologia , Eritropoetina/metabolismo , Receptores da Eritropoetina/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismo , Memória de Longo PrazoRESUMO
Erythropoietin is a cytokine that binds to the Erythropoietin receptor and regulates the formation of erythroid cells during erythropoiesis in the bone marrow. However, many other organs and tissues express Erythropoietin and its receptor, such as the Nervous System, which principally regulates tissue protection. In the Central Nervous System, Erythropoietin is principally expressed by astrocytes, while neurons mainly express Erythropoietin receptors. Moreover, Erythropoietin acts as a pleiotropic molecule with neuroprotective effects, and its mechanisms of signal transduction pathways are defined, and there is a growing interest in its therapeutic potential. This review focuses on the role of Erythropoietin and its relationship with HIF1, PI3/Akt, GSK3B, JAK/STAT, and MAPKs signaling pathways that leads to cell survival after injury in the Central Nervous System. Knowledge of these signaling systems comprehensively could better guide EPO treatment to restoring different SNC alterations mediated by different insults.
Assuntos
Eritropoetina , Fármacos Neuroprotetores , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Humanos , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores da Eritropoetina/metabolismo , Transdução de SinaisRESUMO
Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non-hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression. Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.
Assuntos
Encéfalo/metabolismo , Eritropoetina/metabolismo , Doenças Neurodegenerativas/metabolismo , Neuroproteção/fisiologia , Receptores da Eritropoetina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Eritropoetina/administração & dosagem , Humanos , Doenças Neurodegenerativas/terapia , Neuroproteção/efeitos dos fármacosRESUMO
Chronic kidney disease (CKD) causes anemia by renal damage. In CKD, the kidney is submitted to hypoxia, persistent inflammation, leading to fibrosis and permanent loss of renal function. Human recombinant erythropoietin (rEPO) has been widely used to treat CKD-associated anemia and is known to possess organ-protective properties that are independent from its well-established hematopoietic effects. Nonhematopoietic effects of EPO are mediated by an alternative receptor that is proposed to consist of a heterocomplex between the erythropoietin receptor (EPOR) and the beta common receptor (ßcR). The present study explored the effects of rEPO to prevent renal fibrosis in adenine-induced chronic kidney disease (Ad-CKD) and their association with the expression of the heterodimer EPOR/ßcR. Male Wistar rats were randomized to control group (CTL), adenine-fed rats (Ad-CKD), and Ad-CKD with treatment of rEPO (1050 IU/kg, once weekly for 4 weeks). Ad-CKD rats exhibited anemia, uremia, decreased renal function, increased infiltration of inflammatory cells, tubular atrophy, and fibrosis. rEPO treatment not only corrected anemia but reduced uremia and partially improved renal function as well. In addition, we observed that rEPO diminishes tubular injury, prevents fibrosis deposition, and induces the EPOR/ßcR heteroreceptor. The findings may explain the extrahematopoietic effects of rEPO in CKD and provide new strategies for the treatment of renal fibrosis in CKD.
Assuntos
Fibrose/metabolismo , Fibrose/prevenção & controle , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Western Blotting , Eritropoetina/uso terapêutico , Imunofluorescência , Humanos , Imunoprecipitação , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Eritropoetina/metabolismo , Proteínas Recombinantes/uso terapêuticoRESUMO
The most important activity of erythropoietin (EPO) is the regulation of erythrocyte production by activation of the erythropoietin receptor (EPO-R), which triggers the activation of anti-apoptotic and proliferative responses of erythroid progenitor cells. Additionally, to erythropoietic EPO activity, an antiapoptotic effect has been described in a wide spectrum of tissues. EPO low levels are found in the central nervous system (CNS), while EPO-R is expressed in most CNS cell types. In spite of EPO-R high levels expressed during the hypoxicischemic brain, insufficient production of endogenous cerebral EPO could be the cause of determined circuit alterations that lead to the loss of specific neuronal populations. In the heart, high EPO-R expression in cardiac progenitor cells appears to contribute to myocardial regeneration under EPO stimulation. Several lines of evidence have linked EPO to an antiapoptotic role in CNS and in heart tissue. In this review, an antiapoptotic role of EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death (SUDEP) has been resumed. Additionally, their protective effects could be a new field of research and a novel therapeutic strategy for the early treatment of these conditions and avoid SUDEP.
Assuntos
Epilepsia Resistente a Medicamentos , Eritropoetina , Encéfalo/metabolismo , Sistema Cardiovascular/patologia , Eritropoetina/metabolismo , Humanos , Receptores da Eritropoetina/metabolismo , Morte Súbita Inesperada na EpilepsiaRESUMO
Erythropoietin (EPO) has been linked to cardioprotective effects. However, its effects during the aging process are little known. We investigated the effect of EPO administration on hemodynamic parameters, cardiac function, oxidative damage, and erythropoietin receptor (EPOR) expression pattern in the hypovolemic state. EPO was administered (1000 IU/kg/3 days) and then acute hemorrhage (20% blood loss) was induced in young and adult rats. There was no difference in plasmatic EPO in either age group. The hemodynamic basal condition was similar, without alterations in renal function and hematocrit, in both age groups. After bleeding, both EPO-treated age groups had increased blood pressure at the end of the experimental protocol, being greater in adult animals. EPO attenuated the tachycardic effect. Ejection fraction and fractional shortening were higher in adult EPO-treated rats subjected to hemorrhage. In the left ventricle, young and adult EPO-treated rats subjected to bleeding showed an increased EPOR expression. A different EPOR expression pattern was observed in the adult right atrial tissue, compared with young animals. EPO treatment decreased oxidative damage to lipids in both age groups. EPO treatment before acute hemorrhage improves cardiovascular function during the aging process, which is mediated by different EPOR pattern expression in the heart tissue.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Epoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Fatores Etários , Animais , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Modelos Animais de Doenças , Hemorragia/metabolismo , Hemorragia/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores da Eritropoetina/agonistas , Receptores da Eritropoetina/metabolismoRESUMO
Erythropoietin is a glycoproteic hormone that regulates hematopoiesis by acting on its specific receptor (EpoR). The expression of EpoR in the central nervous system (CNS) suggests a role for this hormone in the brain. Recently, we developed a new Epo variant without hematopoietic activity called EpoL, which showed marked neuroprotective effects against oxidative stress in brain ischemia related models. In this study, we have evaluated the neuroprotective effects of EpoL against oxidative stress induced by chronic treatment with Aß. Our results show that EpoL was neuroprotective against Aß-induced toxicity by a mechanism that implicates EpoR, reduction in reactive oxygen species, and reduction in astrogliosis. Furthermore, EpoL treatment improved calcium handling and SV2 levels. Interestingly, the neuroprotective effect of EpoL against oxidative stress induced by chronic Aß treatment was achieved at a concentration 10 times lower than that of Epo. In conclusion, EpoL, a new variant of Epo without hematopoietic activity, is of potential interest for the treatment of diseases related to oxidative stress in the CNS such as Alzheimer disease.
Assuntos
Eritropoetina/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes/farmacologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Sinalização do Cálcio , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Eritropoetina/genética , Eritropoetina/isolamento & purificação , Cabras , Leite , Fármacos Neuroprotetores/isolamento & purificação , Fragmentos de Peptídeos/química , Multimerização Proteica , Espécies Reativas de Oxigênio/metabolismo , Receptores da Eritropoetina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificaçãoRESUMO
It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.
Assuntos
Injúria Renal Aguda/sangue , Células da Medula Óssea/metabolismo , Células Precursoras Eritroides/metabolismo , Eritropoetina/sangue , Fatores de Crescimento de Fibroblastos/sangue , Injúria Renal Aguda/etiologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoetina/farmacologia , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Estudos Prospectivos , Ratos Sprague-Dawley , Receptores da Eritropoetina/agonistas , Receptores da Eritropoetina/metabolismo , Proteínas Recombinantes/farmacologia , Sepse/sangue , Sepse/complicações , Choque Hemorrágico/sangue , Choque Hemorrágico/complicações , Fatores de Tempo , Regulação para CimaRESUMO
Human erythropoietin is mainly recognized for its hematopoietic function; however, by binding to its receptor (EpoR), it can activate different signaling pathways as STAT, PI3K, MAPK and RAS to increase cellular differentiation or provide neuroprotective effects, among others. A recombinant human erythropoietin variant with low glycosylation and without hematopoietic effect (EpoL) was purified from skimmed goat milk. Recombinant human erythropoietin (Epo) was obtained from CHO cell line and used as control to compare EpoL effects. Neuroprotection studies were performed in PC12 cells and rat hippocampal slices. Cells were pretreated during 1h with EpoL or Epo and exposed to oxidative agents (H2O2 or FCCP); cell viability was assayed at the end of the experiment by the MTT method. Hippocampal slices were exposed to 15min of oxygen and glucose deprivation (OGD) and the neuroprotective drugs EpoL or Epo were incubated for 2h post-OGD in re-oxygenated medium. Cell cultures stressed with oxidative agents, and pretreated with EpoL, showed neuroprotective effects of 30% at a concentration 10 times lower than that of Epo. Moreover, similar differences were observed in OGD ex vivo assays. Neuroprotection elicited by EpoL was lost when an antibody against EpoR was present, indicating that its effect is EpoR-dependent. In conclusion, our results suggest that EpoL has a more potent neuroprotective profile than Epo against oxidative stress, mediated by activation of EpoR, thus EpoL represents an important target to develop a potential biopharmaceutical to treat different central nervous system pathologies related to oxidative stress such as stroke or neurodegenerative diseases.