A Potential Role for Erythropoietin in Focal Permanent Cerebral Ischemia in Mice

Bernaudin, Myriam; Marti, Hugo H.; Roussel, Simon; Divoux, Didier; Nouvelot, A.; MacKenzie, Eric T.; Petit, Edwige

doi:10.1097/00004647-199906000-00007

Cited by 676 publications

(607 citation statements)

References 36 publications

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“…14 Several intracellular signal transduction cascades are involved in the antiapoptotic effects of Epo on erythroblasts including Ras-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), and the Bcl-2 family. 14,15 It is becoming increasingly clear that Epo has additional neuroprotective effects in different in vivo models of brain injury, [16][17][18][19] modulating the same signal transduction cascades that we identified to be involved in RGC death in our MOG-EAE model, the Bcl-2 family and the PI3-K/Akt pathway. 10 Furthermore, Epo has been demonstrated to delay the onset and to reduce the severity of clinical symptoms in an EAE model induced by myelin basic protein (MBP).…”

Section: Introductionmentioning

confidence: 85%

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Sättler¹,

Merkler

Maier³

et al. 2004

Cell Death Differ

164

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In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

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Section: Introductionmentioning

confidence: 85%

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Sättler¹,

Merkler

Maier³

et al. 2004

Cell Death Differ

164

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“…These actions are known to involve several receptors and signaling pathways. Many studies suggest a role of EPOR in tissue protection (Bernaudin et al, 1999;Siren et al, 2001), but the receptor complex mediating EPO hematopoietic effects and EPO neuroprotective actions differs in the affinity for EPO and the associated proteins involved (Masuda et al, 1993). Moreover, CEPO does not seem to bind to the EPOR despite displaying neuroprotective actions (Leist et al, 2004), but Brines et al (2004) recently reported that using knock out (KO) mice for the βcR subunit the neuroprotective effects of both EPO and CEPO were abolished.…”

Section: Discussionmentioning

confidence: 99%

“…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). Within the brain, functional EPORs are expressed by different cell types such as neurons, glial cells and brain capillary endothelial cells (Genc et al, 2004a,b), while the main source of EPO within the CNS itself appears to be the astroglial cells (Bernaudin et al, 2000;Digicaylioglu et al, 1995;Juul et al, 1998;Marti et al, 1996;Masuda et al, 1993).…”

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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“…Recently, apart from its principal function in erythropoiesis, nonhematopoietic functions of EPO such as angiogenic, cardioprotective, and neuroprotective effects have attracted extensive concerned (Kertesz, Wu, Chen, Sucov, & Wu, 2004; Kumral et al., 2011; Tada et al., 2006). Erythropoietin receptor (EPOR) is expressed by a variety of nonhematopoietic cell types such as vascular smooth muscle cells, myocardial cells, brain capillary endothelial cells, and neurons (Acheson, Richards, & de Wit, 2007; Bernaudin et al., 1999; Cianferotti & Brandi, 2014; Wright et al., 2004). EPO can alleviate motor and cognitive deficit, axonal pathology, and neuroinflammation in the models of cerebral ischemia (Villa et al., 2003), experimental autoimmune encephalomyelitis (EAE) (Yuan et al., 2008), and diffuse axonal injury (DAI) (Hellewell, Yan, Alwis, Bye, & Morganti‐Kossmann, 2013).…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

Zhou

Zheng

et al. 2017

Brain and Behavior

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IntroductionTraumatic brain injury (TBI) remains a leading cause of disability and death among young people in China. Unfortunately, no specific pharmacological agents to block the progression of secondary brain injury have been approved for clinical treatment. Recently, neuroprotective effects of erythropoietin (EPO) have been demonstrated in addition to its principal function in erythropoiesis, and hence it is viewed as a potential drug for TBI. In this study, we have investigated the neuroprotective effects of EPO associated with immune/inflammatory modulation in a mouse experimental TBI model.Methods EPO (5000 U/kg body weight, i.p.) was injected at 1 hr, 1, 2, and 3 days after TBI, and its effect on cognitive function, brain edema, immune/inflammatory cells including regulatory T cells (Tregs), neutrophils, CD3+ T cells, and microglia, cytokines including interleukin‐10 (IL‐10), transforming growth factor‐β (TGF‐β), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) were evaluated at different time points after treatment.Results EPO treatment significantly decreased brain edema and improved cognitive function when compared to Saline‐treated mice (p < .05). EPO treatment also significantly increased Tregs level in spleen and injured brain tissue as well as significantly reduced the infiltration and activation of immune/inflammatory cells (neutrophils, CD3+T cells, and microglia) in the injured hemisphere compared to Saline‐treated control animals (p < .05). In addition, ELISA analysis demonstrated that EPO treatment increased the expression of anti‐inflammatory cytokine IL‐10, but decreased the expression of proinflammatory cytokine IL‐1β and TNF‐α in the injured brain tissue (p < .05).ConclusionsThese findings suggest that EPO could improve neurological and cognitive functional outcomes as well as regulate immune/inflammatory reaction in TBI.

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A Potential Role for Erythropoietin in Focal Permanent Cerebral Ischemia in Mice

Cited by 676 publications

References 36 publications

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

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 regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

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