Erythropoietin Is a Paracrine Mediator of Ischemic Tolerance in the Brain: Evidence from an<i>In Vitro</i>Model

Ruscher, Karsten; Freyer, Dorette; Karsch, Maria; Исаев, Н.К.; Megow, Dirk; Sawitzki, Birgit; Priller, Josef; Dirnagl, Ulrich; Meisel, Andreas

doi:10.1523/jneurosci.22-23-10291.2002

Cited by 428 publications

(399 citation statements)

References 64 publications

(86 reference statements)

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“…[85][86][87][88] Recent reports suggest that another HIF family member, HIF-2, is the major inducer of EPO in hypoxia. 39,89 Not only does EPO production by astrocytes have local effects, but ablation of HIF-2 function selectively in astrocytes causes anemia during hypoxia-ischemia, demonstrating the importance of astrocyte EPO production for erythropoiesis.…”

Section: Astrocytes and Epo As A Neuroprotectantmentioning

confidence: 99%

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Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Section: Astrocytes and Epo As A Neuroprotectantmentioning

confidence: 99%

“…2B). Erythropoietin reduces neuronal death with OGD, 86 glutamate toxicity, 91 and NO-induced cell death. 92 Astrocytes contribute to the EPO-mediated neuroprotection, as demonstrated by experiments in which conditioned media taken from hypoxic astrocyte cultures is protective to neurons exposed to OGD.…”

Section: Astrocytes and Epo As A Neuroprotectantmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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“…During brain development, the expression of both EPO and EPOR changes drastically (Buemi et al, 2005;Genc et al, 2004a,b;Juul et al, 1999). Lately, Ruscher et al (2002) hypothesized that EPO has paracrine functions in cerebral ischemia. The neuroprotective effects of EPO appear to be mediated by various mechanisms, including decreased production and/or release of tissue-injuring molecules such as reactive oxygen and nitrogen species and glutamate, modulation of neurotransmission, reversal of vasospasm, attenuation of apoptosis and modulation of inflammation (Brines and Cerami, 2005).…”

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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“…9,16,17 Sublethal hypoxia induces upregulation and nuclear translocation of hypoxia-inducible factor, whose target gene is Epo. [18][19][20][21] Epo stimulates postnatal neovascularization at least in part by enhancing mobilization of EPCs from the bone marrow. 22,23 Epo is also known to enhance mobilization of EPCs from bone marrow and maintain normal endothelial differentiation of retina on ischemic tissue to help the wound healing process.…”

Section: Introductionmentioning

confidence: 99%