Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage

Lee, Sang Kun; Chu, Kon; Sinn, Dong In; Jung, Kwangyun; Kim, Eun Hee; Kim, Se Jeong; Ko, Song Yi; Kim, Manho; Roh, Jae Kyu

doi:10.1111/j.1471-4159.2006.03697.x

Cited by 131 publications

(125 citation statements)

References 69 publications

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“…MAPK3(ERK1), MAPK1(ERK2), STAT4, and FASLG are all overexpressed in the lymphoblasts with the homozygous deletion of 15q13.3. These genes have been associated with encephalopathy, 28,29 and are intermediaries in the neuregulin and relaxin signaling.…”

Section: Q133 Homozygous Microdeletion Syndrome J-b Le Pichon Et Almentioning

confidence: 99%

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Pichon

Kibiryeva

et al. 2013

Eur J Hum Genet

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We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age-and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFa modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-a secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7.

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Section: Q133 Homozygous Microdeletion Syndrome J-b Le Pichon Et Almentioning

confidence: 99%

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Pichon

Kibiryeva

et al. 2013

Eur J Hum Genet

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“…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.…”

mentioning

confidence: 99%

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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“…Although the neuroprotectivity of EPO is associated with multiple mechanisms, including anti-inflammation and anti-apoptosis, the molecular mechanisms underlying these effects remain unclear. It has been shown that EPO binding to its receptor prevents neuronal apoptosis, which involves the activation of janus kinase 2 and the nuclear factor-κB signaling pathways (20). In addition, EPO has also been shown to prevent apoptotic injury through an Akt-dependent mechanism (39).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, studies have demonstrated the beneficial involvement of EPO in ICH, possibly through its anti-inflammatory and anti-apoptotic effects (17)(18)(19)(20). However, the molecular and cellular mechanisms and the signaling pathway underlying these effects remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin reduces brain injury after intracerebral hemorrhagic stroke in rats

Tang

Chen

et al. 2013

Molecular Medicine Reports

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Abstract. Erythropoietin (EPO) has been shown to be neuroprotective in various models of neuronal injury. The aim of the present study was to investigate the beneficial effect of recombinant human EPO (rhEPO) following intracerebral hemorrhage (ICH) and the underlying molecular and cellular mechanisms. ICH was induced using autologous blood injection in adult rats. rhEPO (5000 IU/kg) or vehicle was administered to rats with ICH 2 h following surgery and every 24 h for 1 or 3 days. To study the involvement of the PI3K signaling pathway in the rhEPO-mediated effect, the PI3K inhibitor wortmannin (15 µg/kg), was intravenously administered to rats with ICH 90 min prior to rhEPO treatment. Brain edema was measured 3 days following ICH and behavioral outcomes were measured at 1, 7, 14, 21 and 28 days following ICH using the modified neurological severity score (mNSS) and the corner turn test. Proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, in the ipsilateral striatum were analyzed using an enzyme-linked immunosorbent assay 24 h following ICH. Neuronal apoptosis in the perihematomal area was determined by NeuN and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) double-staining. The results showed that rhEPO treatment reversed ICH, increased brain water content, upregulated proinflammatory cytokines, neuronal loss and apoptosis in the perihematomal area and rescued behavioral deficits in injured rats. Inhibiting the PI3K pathway with wortmannin abolished the rhEPO-mediated neuroprotective effects. Moreover, western blot analysis showed that rhEPO induced the upregulation of Akt phosphorylation and downregulation of glycogen synthase kinase (GSK)-3β phosphorylation, which were reversed by pretreatment with wortmannin, indicating the involvement of PI3K signaling in rhEPO-mediated anti-apoptotic and anti-inflammatory effects following ICH. In conclusion, these results suggested that rhEPO may exert its beneficial effects in ICH through the activation of the PI3K signaling pathway.

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Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage

Cited by 131 publications

References 69 publications

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

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

Erythropoietin reduces brain injury after intracerebral hemorrhagic stroke in rats

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