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

Abstract

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...

Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4

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Minimally Invasive Surgery for Intracerebral Hematoma Evacuation followed by Rosiglitazone Infusion Therapy Increased Perihematomal Occludin, Zonula Occludens-1 Expression and Decreased the Blood Brain Barrier Permeability in Rabbits

“…The expressions of occludin and ZO-1 are closely associated with the degree of BBB damage, and are indicator of BBB destruction [20]. Angiogenic cerebral edema induced by BBB disruption is associated with the clinical prognosis in ICH patients [21,22]. …”

“…Research Guofeng Wu, Mengzhou Xue revealed that Erythropoietin protects BBB from disruption after ICH, and that the main targets are the TJ proteins occludin and ZO-1 [21]. However, little information is known about the changes of occludin and ZO-1 expressions in perihemotomal brain tissues after MIS for ICH.…”

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