The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

Xiang, Jianming; Routhe, Lisa Juul; Wilkinson, David; Hua, Ya; Moos, Torben; Xi, Guohua; Keep, Richard F.

doi:10.1186/s12987-017-0056-3

Cited by 41 publications

(38 citation statements)

References 148 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…When blood flow to the brain is interrupted during ischemic stroke, which is one of the leading causes of death and disability [26], the depletion of oxygen and nutrients in the ischemic area triggers a cascade of detrimental processes leading to neuronal cell death, neuroinflammation, and cerebrovascular disruption [15,[27][28][29]. There have been extensive attempts to understand the pathophysiology of ischemic stroke [18,28,[30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Kim

et al. 2020

Fluids Barriers CNS

View full text Add to dashboard Cite

Background: The blood-brain barrier (BBB) maintains homeostasis of the brain environment by tightly regulating the entry of substances from systemic circulation. A breach in the BBB results in increased permeability to potentially toxic substances and is an important contributor to amplification of ischemic brain damage. The precise molecular pathways that result in impairment of BBB integrity remain to be elucidated. Autophagy is a degradation pathway that clears damaged or unnecessary proteins from cells. However, excessive autophagy can lead to cellular dysfunction and death under pathological conditions. Methods:In this study, we investigated whether autophagy is involved in BBB disruption in ischemia, using in vitro cells and in vivo rat models. We used brain endothelial bEnd.3 cells and oxygen glucose deprivation (OGD) to simulate ischemia in culture, along with a rat ischemic stroke model to evaluate the role of autophagy in BBB disruption during cerebral ischemia.Results: OGD 18 h induced cellular dysfunction, and increased permeability with degradation of occludin and activation of autophagy pathways in brain endothelial cells. Immunostaining revealed that occludin degradation is co-localized with ischemic autophagosomes. OGD-induced occludin degradation and permeability changes were significantly decreased by inhibition of autophagy using 3-methyladenine (3-MA). Enhanced autophagic activity and loss of occludin were also observed in brain capillaries isolated from rats with middle cerebral artery occlusion (MCAO). Intravenous administration of 3-MA inhibited these molecular changes in brain capillaries, and recovered the increased permeability as determined using Evans blue. Conclusions:Our findings provide evidence that autophagy plays an important role in ischemia-induced occludin degradation and loss of BBB integrity.

show abstract

Section: Discussionmentioning

confidence: 99%

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Kim

et al. 2020

Fluids Barriers CNS

View full text Add to dashboard Cite

show abstract

“…Cerebrospinal fluid is primarily produced in the choroid plexuses, which consist of many capillaries and are important components of the blood‐CSF barrier . VE‐cadherin is a crucial component of adherent junctions (AJs) in vascular endothelial cells, which regulates water and solutes in and out vessels and forms the restrictive endothelial barrier .…”

Section: Discussionmentioning

confidence: 99%

“…Cerebrospinal fluid (CSF) is mainly produced in the choroid plexuses, which consist of plenty of capillaries constructing the blood-CSF barrier. 11 Choroid plexuses dysfunction would be expected to cause an increase in the production of CSF. 12,13 The transmembrane protein vascular endothelial-cadherin (VE-cadherin) exists in the central nervous system endothelium.…”

mentioning

confidence: 99%

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Hao

Zhang

et al. 2019

CNS Neurosci Ther

View full text Add to dashboard Cite

Summary Aims Previous studies indicated that intraventricular injection of thrombin would induce hydrocephalus. But how thrombin works in this process remains unclear. Since cadherin plays a critical role in hydrocephalus, we aimed to explore the mechanisms of how thrombin acted on choroid plexus vascular endothelium and how thrombin interacted with vascular endothelial‐cadherin (VE‐cadherin) during hydrocephalus. Methods There were two parts in this study. Firstly, rats received an injection of saline or thrombin into the right lateral ventricle. Magnetic resonance imaging was applied to measure the lateral ventricle volumes. Albumin leakage and Evans blue content were assessed to test the blood‐brain barrier function. Immunofluorescence and Western blot were applied to detect the location and the expression of VE‐cadherin. Secondly, we observed the roles of protease‐activated receptors‐1 (PAR1) inhibitor (SCH79797), Src inhibitor (PP2), p21‐activated kinase‐1 (PAK1) inhibitor (IPA3) in the thrombin‐induced hydrocephalus, and their effects on the regulation of VE‐cadherin. Results Our study demonstrated that intraventricular injection of thrombin caused significant downregulation of VE‐cadherin in choroid plexus and dilation of ventricles. In addition, the inhibition of PAR1/p‐Src/p‐PAK1 pathway reversed the decrease of VE‐cadherin and attenuated thrombin‐induced hydrocephalus. Conclusions Our results suggested that the thrombin‐induced hydrocephalus was associated with the inhibition of VE‐cadherin via the PAR1/p‐Src/p‐PAK1 pathway.

show abstract

“…It should be noted that surprisingly little is known about how the choroid plexuses are impacted by IVH 66 . Such changes may impact fluid secretion (e.g.…”

Section: Ivh-induced Brain Injurymentioning

confidence: 99%

Challenges for intraventricular hemorrhage research and emerging therapeutic targets

Garton

Hua

Xiang

et al. 2017

Expert Opinion on Therapeutic Targets

Self Cite

View full text Add to dashboard Cite

Introduction – Intraventricular hemorrhage (IVH) affects both premature infants and adults. In both demographics, it has high mortality and morbidity. There is no FDA approved therapy that improves neurological outcome in either population highlighting the need for additional focus on therapeutic targets and treatments emerging from preclinical studies. Areas Covered – IVH induces both initial injury linked to the physical effects of the blood (mass effect) and secondary injury linked to the brain response to the hemorrhage. Preclinical studies have identified multiple secondary injury mechanisms following IVH, and particularly the role of blood components (e.g. hemoglobin, iron, thrombin). This review, with an emphasis on pre-clinical IVH research, highlights therapeutic targets and treatments that may be of use in prevention, acute care, or repair of damage. Expert Opinion – An IVH is a potentially devastating event. Progress has been made in elucidating injury mechanisms, but this has still to translate to the clinic. Some pathways involved in injury also have beneficial effects (coagulation cascade/inflammation). A greater understanding of the downstream pathways involved in those pathways may allow therapeutic development. Iron chelation (deferoxamine) is in clinical trial for intracerebral hemorrhage and preclinical data suggest it may be a potential treatment for IVH.

show abstract

The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury

Cited by 41 publications

References 148 publications

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Thrombin disrupts vascular endothelial‐cadherin and leads to hydrocephalus via protease‐activated receptors‐1 pathway

Challenges for intraventricular hemorrhage research and emerging therapeutic targets

Contact Info

Product

Resources

About