Erythropoietin Prevents Blood Brain Barrier Damage Induced by Focal Cerebral Ischemia in Mice

Liu, Ying; Lu, Zhongyang; Ogle, Molly E.; Wei, Ling

doi:10.1007/s11064-007-9387-9

Cited by 53 publications

(35 citation statements)

References 35 publications

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“…5,6,27 These results reveal the effects of EPO on BBB under pathological conditions, in accordance with findings of this study. We further investigated the mechanisms involved in order to determine whether EPO elicited its protective effects by regulating the expression of AQP4.…”

Section: Erythropoietin Protects Bbb From Disruptionsupporting

confidence: 91%

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Chu

Ding

Tang

et al. 2014

Laboratory Investigation

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Erythropoietin (EPO) has protective effects against many neurological diseases, including intracerebral hemorrhage (ICH). Here, we aimed to test EPO's effects on blood-brain barrier (BBB) disruption morphologically and functionally following ICH, which has not been well investigated. We also examined whether the effects were dependent on aquaporin-4 (AQP4). We detected the expression of perihematomal AQP4 and EPO receptor (EPOR) induced by EPO injection at 1, 3 and 7 days after ICH. We also examined the effects of EPO on BBB disruption by ICH in wild-type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the related signal transduction pathways via astrocyte cultures. We found that EPO highly increased perihematomal AQP4 and EPOR expression. Specifically, EPO led to BBB protection in both types of mice by functionally reducing brain edema and BBB permeability, as well as morphologically suppressing tight junction (TJ) opening and endothelial cell swelling, and increasing expression of the TJ proteins occludin and zonula occluden-1 (ZO-1). Statistical analysis indicated that AQP4 was required for these effects. In addition, EPO upregulated phosphorylation of C-Jun amino-terminal kinase (JNK) and p38-mitogenactivated protein kinase (MAPK) as well as EPOR and AQP4 proteins in cultured astrocytes. The latter was inhibited by JNK and p38-MAPK inhibitors. Our data suggest that EPO protects BBB from disruption after ICH and that the main targets are the TJ proteins occludin and ZO-1. The effects of EPO are associated with increased levels of AQP4, and may occur through activation of JNK and p38-MAPK pathways after binding to EPOR. Erythropoietin (EPO) was originally recognized as a humoral mediator involved in the maturation and proliferation of erythroid progenitor cells but is now appreciated for its neuroprotective effects in the central nervous system (CNS) as well. There has been a great deal of research confirming the protective effect of EPO in cerebral ischemic models, the mechanisms of which include apoptosis reduction, inflammation inhibition, angiogenesis enhancement and cerebral blood flow restoration. 1,2 In recent years, studies have been conducted to determine EPO's effects on intracerebral hemorrhage (ICH), another type of stroke. 3,4 However, the mechanisms involved need further investigation.Disruption of the blood-brain barrier (BBB) is an important pathophysiological change after ICH and contributes to vasogenic brain edema formation, which is often serious and leads to poor prognosis. Previous research on EPO and BBB mainly focused on cerebral ischemic models, indicating that BBB disruption induced by middle cerebral artery occlusion can be attenuated by EPO. 5,6 So far, there has only been one study describing how EPO acts on BBB disruption resulting from ICH, and this study reveals that EPO decreased BBB permeability at 3 days after ICH. 7 However, this effect was observed for only one isolated time point without dynamic observation a...

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Section: Erythropoietin Protects Bbb From Disruptionsupporting

confidence: 91%

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Chu

Ding

Tang

et al. 2014

Laboratory Investigation

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“…Epo Protected Enterocyte Barrier Function and ZO-1 Localization from Inflammatory Cytokine-induced Damages-Human milk is protective against NEC, and Epo is a human milk factor that has been shown to protect cell-cell barrier in endothelial cells and the blood-brain barrier in animals (15,16). We hypothesized that Epo may similarly protect intestinal epithelial barrier function.…”

Section: Zo-1 Silencing Impaired Ter and Barrier Function Inmentioning

confidence: 99%

“…Erythropoietin (Epo) is a human milk factor (14). Although first described as a major regulator of erythropoiesis, Epo exhibits additional biological activities, including protection of endothelial cell-cell and blood-brain barriers (15,16). Functional Epo receptors are present on the luminal side of villi in fetal and neonatal human and rat intestines (17,18), suggesting physiological roles of Epo in the developing gut.…”

mentioning

confidence: 99%

Erythropoietin Protects Intestinal Epithelial Barrier Function and Lowers the Incidence of Experimental Neonatal Necrotizing Enterocolitis

Shiou

Yu²,

Chen³

et al. 2011

Journal of Biological Chemistry

105

110

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“…Some authors have suggested that its local expression in the brain is unrelated to CM, 78 whereas others find it strongly associated with protection against neurologic sequelae in survivors of CM. 79 EPO is an anti-apoptotic hormone that protects endothelial cells, 80 thereby conserving BBB function in a stroke model 81 . Another and perhaps more important property of EPO in the context of CM is its stimulatory effect on nitric oxide secretion caused by endothelial nitric oxide synthase, 82 which improves perfusion under experimental conditions.…”

Section: Hypoxia and Cerebralmentioning

confidence: 99%

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

Hempel

Combes

Hunt

et al. 2011

The American Journal of Pathology

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Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice, and two models of malaria without neurologic signs, P. berghei K173 in CBA mice and P. berghei ANKA in BALB/c mice. Hypoxia was demonstrated in brain sections using intravenous pimonidazole and staining with hypoxia-inducible factor-1␣-specific antibody. Cytopathic hypoxia was studied using poly (ADP-ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia. These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy.

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Erythropoietin Prevents Blood Brain Barrier Damage Induced by Focal Cerebral Ischemia in Mice

Cited by 53 publications

References 35 publications

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Erythropoietin Protects Intestinal Epithelial Barrier Function and Lowers the Incidence of Experimental Neonatal Necrotizing Enterocolitis

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

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