Effects of Erythropoietin on Blood-Brain Barrier Disruption in Focal Cerebral Ischemia

Z., Oak; Hunter, Christine; Liu, Xia; Weiss, Harvey R.

doi:10.1159/000127839

Cited by 24 publications

(15 citation statements)

References 64 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: 92%

“…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 and has not yet been supported by other research.…”

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confidence: 79%

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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: 92%

mentioning

confidence: 79%

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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“…Indeed many growth factors secreted by both astrocytes and pericytes are also likely to modulate permeability of the BBB although current evidence is very limited. Reports of secretion of TGF‐β (Garcia et al, 2004; Dohgu et al, 2005), erythropoietin (Chavez et al, 2006; Chi et al, 2008), glial derived neurotrophic factor and neurotrophin (Lin et al, 2006) by astrocytes and/or pericytes during cerebral hypoxia/ischemia reveals the diversity of hypoxically regulated factors that might promote barrier maintenance and cell survival in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Maintaining blood–brain barrier integrity: Pericytes perform better than astrocytes during prolonged oxygen deprivation

Ahmad

Gassmann

Ogunshola

2008

Journal Cellular Physiology

126

102

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The blood-brain barrier (BBB), consisting of specialized endothelial cells surrounded by astrocytes and pericytes, plays a crucial role in brain homeostasis. Many cerebrovascular diseases are associated with BBB breakdown and oxygen (O(2)) deprivation constitutes a critical factor that onsets its disruption. We investigated the impact of astrocytes and pericytes on brain endothelial cell permeability and survival during different degrees of O(2) deprivation. Prolonged exposure to 1% O(2) caused barrier breakdown and exposure to 0.1% O(2) dramatically accelerated disruption and induced cell death, mediated at least in part via caspase-3 activation. Reoxygenation allowed only cells exposed to 1% O(2) to re-establish barrier function. Notably co-culture with astrocytes and pericytes substantially enhanced barrier function under normoxic conditions, and produced differential responses during O(2) deprivation. At 1% O(2) astrocytes partially maintained barrier integrity whereas pericytes accelerated its disruption in the short-term, having positive effects only after prolonged exposure. Unexpectedly, at 0.1% O(2) pericytes were more effective than astrocytes in preserving barrier function although the protection afforded by both cells involved inhibition of caspase-3 pathways. Furthermore, cell-specific regulation of auto- and paracrine VEGF signaling pathways were also in part responsible for the differential modulation of barrier function. Our data suggests that cellular cross-talk within the neurovascular unit is crucial for preservation of barrier integrity and that pericytes, not astrocytes, play a significant role during severe and prolonged O(2) deprivation.

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“…Systemic administration of EPO can cross the blood-brain barrier (BBB) by a transcellular receptor [6,7], and act by direct binding with partner receptor on different cells within the central nervous system (CNS). In animal models of brain traumatic injury, cerebral ischemia, spinal cord injury, Parkinson's disease, and even dementia, EPO improves the clinical symptoms by reducing oxidative stress, promoting the angiogenesis and neurogenesis, and keeping the integrity of the BBB [8][9][10][11][12][13][14][15][16][17][18], thereby indicating that EPO has the potential to provide neuroprotection in the brain.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effect of Erythropoietin Therapy on Experimental Autoimmune Encephalomyelitis

Zhang

Xiao³

2012

International Journal of Neuroscience

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Previous studies report that erythropoietin (EPO) has a neuroprotective role in some neurodegenerative diseases, but the mechanisms are not completely elucidated. The aim of this study was to investigate whether EPO exerts neuroprotective role in experimental autoimmune encephalomyelitis (EAE) via the routes of anti-inflammation. We established an EAE mice model treated intraperitoneally with EPO at the dose of 5,000 IU/kg on schedule, and recorded the clinical score and weight fluctuation. The infiltration of inflammatory cells in the spinal cord of EAE mice was observed with hemotoxylin and eosin (HE) staining, and the levels of IL-10, IFN-γ, IL-17, and MHC-II in central nervous system (CNS)-infiltrating cells and peripheral mononuclear cells were detected by flow cytometry or ELISA. EPO therapy ameliorates clinical signs of EAE mice, inhibits the body weight loss, and decreases the infiltration of inflammatory cells in spinal cords. IL-17 and IFN-γ are reduced, while IL-10 is not increased significantly, in both CNS-infiltrating cells and peripheral mononuclear cells of EPO-treated EAE mice, as compared with EAE control group. EPO also reduces the expression of MHC-II on peripheral antigen presentation cells. Our results indicate that EPO exerts a beneficial role in EAE by inhibiting the levels of IL-17 and IFN-γ in peripheral splenic cells and CNS-infiltrating cells.

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Effects of Erythropoietin on Blood-Brain Barrier Disruption in Focal Cerebral Ischemia

Cited by 24 publications

References 64 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

Maintaining blood–brain barrier integrity: Pericytes perform better than astrocytes during prolonged oxygen deprivation

Anti-Inflammatory Effect of Erythropoietin Therapy on Experimental Autoimmune Encephalomyelitis

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