Erythropoietin and the brain: from neurodevelopment to neuroprotection

Buemi, Michele; Cavallaro, Emanuela; Floccari, Fulvio; Sturiale, Alessio; Aloisi, Carmela; Trimarchi, Michele; Grasso, Giovanni; Corica, Francesco; Frisina, N

doi:10.1042/cs1030275

Cited by 97 publications

(50 citation statements)

References 73 publications

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“…Traditionally, EPO has been seen as a stimulator of hematopoiesis and produced in kidney, liver and spleen in response to hypoxia, but it is also expressed in the uterus (Davis et al, 2003) and in brain (Genc et al, 2004a,b;Sasaki, 2003). In the brain, EPO is highly expressed in development (Buemi et al, 2002;Nagai et al, 2001). In the mature brain, expression of EPO appears to be upregulated by oxidative or nitrosative stress (Bernaudin et al, 1999(Bernaudin et al, , 2000Chong et al, 2003;Digicaylioglu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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In addition to its well-known hematopoietic effects, erythropoietin (EPO) also has neuroprotective properties. However, hematopoietic side effects are unwanted for neuroprotection, underlining the need for EPO-like compounds with selective neuroprotective actions. One such compound, devoid of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate (NMDA) excitotoxicity. Hippocampal slice cultures were pretreated for 24 h with 100 IU/ml EPO (= 26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49 ± 3 or 35 ± 8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33 ± 5 and 15 ± 8%, respectively, in the OGD and NMDA exposed cultures. To elucidate a possible mechanism involved in EPO and CEPO neuroprotection against OGD, the integrity of α-II-spectrin cytoskeletal protein was studied. Both EPO and CEPO significantly reduced formation of spectrin cleavage products in the OGD model. We conclude that CEPO is at least as efficient neuroprotectant as EPO when excitotoxicity is modeled in mouse hippocampal slice cultures.

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Section: Introductionmentioning

confidence: 99%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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“…However, Epo and EpoR were recently found to be expressed in other tissues including the nervous system, implying a role of this haematopoietic cytokine in the function of the brain [2][3][4]. Erythropoietin is described as a neuroprotective factor during cerebral ischemia (see [1] for review), experimental brain injury [5], hypoxia [6] and brain haemorrage [7], which shows its importance in the functioning of the brain. Several lines of evidence indicate that the hippocampus is influenced by Epo.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro

Wójtowicz

Mozrzymas

2008

Cellular and Molecular Biology Letters

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Erythropoietin is a potent regulator of erythropoiesis. It acts via the specific membrane receptor (EpoR). Erythropoietin is also known to be present in the central nervous system, and its concentration and the expression of EpoR change during development, which raises the possibility that this modulator might be involved in the regulation of neuronal functions in the developing brain. The GABAergic system undergoes profound changes during development and is particularly susceptible to modulation by endogenous factors. Therefore, we decided to investigate the impact of Epo on GABAergic transmission in hippocampal neurons developing in vitro. An analysis of miniature IPSCs (mIPSCs) revealed that a long-term treatment with Epo (48 or 72 h) resulted in a major acceleration of the decaying phase of these currents while the amplitude and current frequency remained unchanged. Interestingly, this effect was restricted to the youngest considered age group (6-8 DIV), indicating that Epomediated modulation of mIPSCs depends on the developmental stage of the neurons. We conclude that Epo may exert a modulatory action on GABAergic transmission in developing neural networks.

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“…6,7,26 A prolongation of the increase over time of plasma Epo is observed in MCAO rats 6 hours after reperfusion, followed by moderate polycythemia 2 to 7 days after reperfusion. The fact that Epo levels increased only transiently in the presence of persistent hypoxemia is consistent with observations in other models, 8,27,28 and this may be explained, at least in part, by cellular adaptation to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Transient Middle Cerebral Artery Occlusion Influence on Systemic Oxygen Homeostasis and Erythropoiesis in Wistar Rats

Gendron

Kouassi²,

Nuara³

et al. 2004

Stroke

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Background and Purpose-Systemic hypoxia is a common complication in stroke patients and may exacerbate ischemic brain damage. Expression of the hypoxia-inducible cytokine erythropoietin (Epo) is upregulated in the brain in both stroke patients and in animal stroke models and exerts local neuroprotective effects in the ischemic brain. Epo is also well known to stimulate red blood cell (RBC) production. The purpose of the present study was to evaluate whether poststroke systemic hypoxia is present in the rat model and whether it is associated with increased peripheral Epo and RBC production. Methods-Wistar rats underwent 1-hour transient middle cerebral artery occlusion (MCAO) under mechanical ventilation, followed by reperfusion without further ventilation. Groups of MCAO and sham-operated animals were evaluated at extended times after reperfusion for assessment of arterial blood gases, plasma Epo, and complete blood count. Results-Arterial oxygen saturation was significantly lower in the infarct group between 6 and 24 hours after reperfusion (Pϭ0.0005), and plasma Epo levels were increased 6 hours after reperfusion (PϽ0.05). RBC counts and hematocrit were transiently increased 2 to 7 days after reperfusion in animals with MCAO compared with sham. Maximal increases were seen at day 7 (22% and 16% increases of RBC count and hematocrit, respectively; PϽ0.001). In contrast, the white blood cell counts in animals with MCAO decreased by Ͼ30% in the same time period. Conclusions-Plasma Epo levels, RBC counts, and hematocrit are all increased in response to systemic hypoxia after cerebral ischemia in rats. Key Words: hypoxia Ⅲ hematocrit Ⅲ stroke C linical observations indicate that hypoxia is a common complication of stroke in the acute phase and for hours to days after stroke onset. 1,2 Even in stroke patients who appear normoxic during the day, 25% develop hypoxia at night. 3 Studies in rats using intraluminal filament transient middle cerebral artery occlusion (MCAO) and graded levels of hypoxia have shown that hypoxia exacerbates ischemic brain damage. 4 It is not known whether animals with MCAO spontaneously develop systemic hypoxia after a stroke, but this might be expected.Erythropoietin (Epo) is a hypoxia-inducible cytokine, originally identified as a kidney-derived stimulator of erythroid progenitor cell proliferation and differentiation. 5,6 Increased synthesis of Epo is known to stimulate the production of red blood cells (RBCs), thereby increasing oxygen delivery to tissues as a mechanism of physiological adaptation to hypoxia. 7,8 Recent studies have shown that Epo and its receptor (EpoR) are expressed in rodent and human brain tissues. 9,10 Epo system expression is upregulated in the ischemic brain after MCAO in rodents 11,12 and in human autopsy brains with ischemic infarcts or general hypoxic damage. 13 Neutralization of endogenous brain Epo by administration of soluble EpoR potentiates ischemic brain injury in a rodent MCAO stroke model, 14,15 suggesting a role for the brain Epo system in neuroprotecti...

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Erythropoietin and the brain: from neurodevelopment to neuroprotection

Cited by 97 publications

References 73 publications

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro

Transient Middle Cerebral Artery Occlusion Influence on Systemic Oxygen Homeostasis and Erythropoiesis in Wistar Rats

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