Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain

Sirén, Anna‐Leena; Knerlich, Friederike; Poser, W.; Gleiter, Christoph H.; Brück, Wolfgang; Ehrenreich, Hannelore

doi:10.1007/s004010000297

Cited by 313 publications

(116 citation statements)

References 19 publications

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“…In fact, both EPO and its receptor are expressed in various regions of the brain and their expression increased during and after ischemia (Sirén et al, 2001). Furthermore, EPO administration after ischemic stroke or TBI increased BDNF and VEGF expression and improved functional recovery (Wang et al, 2004; Xiong et al, 2011b).…”

Section: Pro-inflammatory Cytokine and Bdnf Interactions Following Stmentioning

confidence: 99%

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

Audet¹,

Anisman²

2013

Front. Cell. Neurosci.

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The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses.

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Section: Pro-inflammatory Cytokine and Bdnf Interactions Following Stmentioning

confidence: 99%

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

Audet¹,

Anisman²

2013

Front. Cell. Neurosci.

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“…Erythropoietin (EPO) is a 30.4 kDa glycoprotein, which stimulates erythropoiesis and is used as a treatment for anemia (Fisher 2010). Systemically administered EPO can cross the disrupted blood-brain barrier in stroke and has repeatedly been shown to reduce infarct volumes in animal models of ischemic stroke (Brines et al 2000;Siren et al 2001;Villa et al 2003;Yu et al 2005;Wakida et al 2007;Wang et al 2007;Minnerup et al 2009). Mechanistically, EPO attenuates apoptotic neuronal death, cytokine production and inflammation in rat models of ischemia (Villa et al 2003;Wang et al 2007).…”

mentioning

confidence: 99%

Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia

Komnig

Gertz

Habib

et al. 2018

Journal of Neurochemistry

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Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease. Erythropoietin (EPO) has been studied as a therapeutic strategy in ischemic stroke. Erythropoietin stimulates the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway, which regulates Faim2 expression. Therefore, up-regulation of Faim2 may contribute to neuroprotection by EPO. Male Faim2-deficient mice (Faim2 ) and wild-type littermates (WT) were subjected to 30 min of middle cerebral artery occlusion (MCAo) followed by 72 h of reperfusion. EPO was applied before (30 min) and after (24 and 48 h) MCAo. In WT mice application of EPO at a low dose (5000 U/kg) significantly reduced stroke volume, whereas treatment with high dose (90 000 U/kg) did not. In Faim2 animals administration of low-dose EPO did not result in a significant reduction in stroke volume. Faim2 expression as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) increased after low-dose EPO but not with high dose. An extensive phenotyping including analysis of cerebral vessel architecture did not reveal confounding differences between the genotypes. In human post-mortem brain Faim2 displayed a differential expression in areas of penumbral ischemia. Faim2 up-regulation may contribute to the neuroprotective effects of low-dose erythropoietin in transient brain ischemia. The dose-dependency may explain mixed effects of erythropoietin observed in clinical stroke trials.

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“…Erythropoietin (EPO) has emerged as a potent neuroprotectant in vivo and in vitro (Morishita et al 1997;Bernaudin et al 1999;Siren et al 2001a). In the brain, EPO gene expression is regulated by the transcription factor hypoxiainducible factor-1 (HIF-1), which is activated by a variety of stressors, including hypoxia (Semenza 2000).…”

mentioning

confidence: 99%

Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitro

Liu¹,

Suzuki²,

Guo³

et al. 2006

Journal of Neurochemistry

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This study was designed to investigate the neuroprotective effect of intrinsic and extrinsic erythropoietin (EPO) against hypoxia/ischemia, and determine the optimal time-window with respect to the EPO-induced neuroprotection. Experiments were conducted using primary mixed neuronal/astrocytic cultures and neuron-rich cultures. Hypoxia (2%) induces hypoxia-inducible factor-1a (HIF-1a) activity followed by strong EPO expression in mixed cultures and weak expression in neuron-rich cultures as documented by both western blot and RT-PCR. Immunoreactive EPO was strongly detected in astrocytes, whereas EPOR was only detected in neurons. Neurons were significantly damaged in neuron-rich cultures but were distinctly rescued in mixed cultures. Application of recombinant human EPO (rhEPO) (0.1 U/mL) within 6 h before or after hypoxia significantly increased neuronal survival compared with no rhEPO treatment. Application of rhEPO after onset of reoxygenation achieved the maximal neuronal protection against ischemia/reperfusion injury (6 h hypoxia followed 24 h reoxygenation). Our results indicate that HIF-1a induces EPO gene released by astrocytes and acts as an essential mediator of neuroprotection, prove the protective role of intrinsic astrocytic-neuronal signaling pathway in hypoxic/ischemic injury and demonstrate an optimal therapeutic time-window of extrinsic rhEPO in ischemia/reperfusion injury in vitro. The results point to the potential beneficial effects of HIF-1a and EPO for the possible treatment of stroke. Keywords: erythropoietin, hypoxia-inducible factor-1, hypoxia/ischemia injury, neuroprotection. Erythropoietin (EPO) has emerged as a potent neuroprotectant in vivo and in vitro (Morishita et al. 1997;Bernaudin et al. 1999;Siren et al. 2001a). In the brain, EPO gene expression is regulated by the transcription factor hypoxiainducible factor-1 (HIF-1), which is activated by a variety of stressors, including hypoxia (Semenza 2000). EPO-induced neuroprotection is mediated by interaction with the cognate receptor EPOR (Chong et al. 2002;Marti 2004). The main cellular source of intrinsic EPO in the brain appears to be astrocytes (Masuda et al. 1994;Marti et al. 1996). In addition Bernaudin et al. (2000) provided direct evidence that not only astrocytes but also neurons express and produce EPO after hypoxia.However, there are no studies that compared the EPO expression levels and the neuroprotective effect between mixed neuronal/astrocytic cultures and neuron-rich cultures. In the present study, we determined EPO expression levels and its neuroprotective effect using both mixed neuronal/astrocytic cultures and neuron-rich cultures exposed to hypoxia and reoxygenation. We considered that the in vitro model of mixed culture might be more physiological than separate cultures for addressing the protective role of intrinsic astrocytic-neuronal signaling in hypoxic/ischemic injury. Furthermore, we compared neuronal survival in the presence or absence of antibodies against EPOR to examine whether neuroprotection i...

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Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain

Cited by 313 publications

References 19 publications

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia

Intrinsic and extrinsic erythropoietin enhances neuroprotection against ischemia and reperfusion injury in vitro

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