Exacerbated brain edema in a rat streptozotocin model of hyperglycemic ischemic stroke: Evidence for involvement of blood–brain barrier Na–K–Cl cotransport and Na/H exchange

Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood–brain barrier (BBB) Na–K–Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.

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High glucose-induced effects on Na+-K+-Cl- cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII and SPAK/OSR1

AJP Cell Physiology ◽

10.1152/ajpcell.00177.2019 ◽

2021 ◽

Author(s):

Nicholas R. Klug ◽

Olga V. Chechneva ◽

Benjamin Y. Hung ◽

Martha E. O'Donnell

Keyword(s):

Blood Brain Barrier ◽

High Glucose ◽

Artery Occlusion ◽

Brain Barrier ◽

Microvascular Endothelial Cell ◽

Edema Formation ◽

Kinase C ◽

Blood Brain ◽

Transport Of Ions ◽

Cerebral Artery Occlusion

Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Na+-K+-2Cl- cotransport (NKCC) and Na+/H+ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCβII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCβII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCβII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCβII abundance or phosphorylation (activity) after 24 or 48 hr HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCβII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.

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Evidence for blood‐brain barrier Na‐K‐Cl cotransport, Na/H exchange and Na‐HCO 3 cotransport involvement in hyperglycemia exacerbation of cerebral edema formation in ischemic stroke (685.3)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.685.3 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Olga Chechneva ◽

Natalie Yuen ◽

Yi‐Chen Tsai ◽

Yi‐Je Chen ◽

Steven Anderson ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Cerebral Edema ◽

Brain Barrier ◽

Edema Formation ◽

Blood Brain

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Cerebral Edema Formation After Stroke: Emphasis on Blood–Brain Barrier and the Lymphatic Drainage System of the Brain

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.716825 ◽

2021 ◽

Vol 15 ◽

Author(s):

Sichao Chen ◽

Linqian Shao ◽

Li Ma

Keyword(s):

Blood Brain Barrier ◽

Cerebral Edema ◽

Lymphatic System ◽

Vasogenic Edema ◽

Lymphatic Vessels ◽

Drainage System ◽

Brain Barrier ◽

Edema Formation ◽

Blood Brain ◽

The Brain

Brain edema is a severe stroke complication that is associated with prolonged hospitalization and poor outcomes. Swollen tissues in the brain compromise cerebral perfusion and may also result in transtentorial herniation. As a physical and biochemical barrier between the peripheral circulation and the central nervous system (CNS), the blood–brain barrier (BBB) plays a vital role in maintaining the stable microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the dysfunction of the BBB results in increased paracellular permeability, directly contributing to the extravasation of blood components into the brain and causing cerebral vasogenic edema. Recent studies have led to the discovery of the glymphatic system and meningeal lymphatic vessels, which provide a channel for cerebrospinal fluid (CSF) to enter the brain and drain to nearby lymph nodes and communicate with the peripheral immune system, modulating immune surveillance and brain responses. A deeper understanding of the function of the cerebral lymphatic system calls into question the known mechanisms of cerebral edema after stroke. In this review, we first discuss how BBB disruption after stroke can cause or contribute to cerebral edema from the perspective of molecular and cellular pathophysiology. Finally, we discuss how the cerebral lymphatic system participates in the formation of cerebral edema after stroke and summarize the pathophysiological process of cerebral edema formation after stroke from the two directions of the BBB and cerebral lymphatic system.

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Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Blood ◽

10.1182/blood-2012-06-440057 ◽

2012 ◽

Vol 120 (19) ◽

pp. 4082-4092 ◽

Cited By ~ 85

Author(s):

Friederike Langhauser ◽

Eva Göb ◽

Peter Kraft ◽

Christian Geis ◽

Joachim Schmitt ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Thrombus Formation ◽

Therapeutic Interventions ◽

Brain Barrier ◽

Edema Formation ◽

Kinin System ◽

Local Inflammatory Response ◽

Blood Brain ◽

Blood Brain Barrier Damage

Abstract Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng−/− mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases.

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Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice

PLoS ONE ◽

10.1371/journal.pone.0015106 ◽

2010 ◽

Vol 5 (12) ◽

pp. e15106 ◽

Cited By ~ 9

Author(s):

Peter Kraft ◽

Peter Michael Benz ◽

Madeleine Austinat ◽

Marc Elmar Brede ◽

Kai Schuh ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Edema Formation ◽

Blood Brain ◽

Blood Brain Barrier Damage

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Intravenous HOE-642 Reduces Brain Edema and Na Uptake in the Rat Permanent Middle Cerebral Artery Occlusion Model of Stroke: Evidence for Participation of the Blood–Brain Barrier Na/H Exchanger

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.160 ◽

2012 ◽

Vol 33 (2) ◽

pp. 225-234 ◽

Cited By ~ 42

Author(s):

Martha E O'Donnell ◽

Yi-Je Chen ◽

Tina I Lam ◽

Kelleen C Taylor ◽

Jeffrey H Walton ◽

...

Keyword(s):

Ischemic Stroke ◽

Magnetic Resonance ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Brain Edema ◽

Cerebral Edema ◽

Artery Occlusion ◽

Edema Formation ◽

Cerebral Artery Occlusion ◽

Na Uptake

Cerebral edema forms in the early hours of ischemic stroke by processes involving increased transport of Na and Cl from blood into brain across an intact blood–brain barrier (BBB). Our previous studies provided evidence that the BBB Na–K–Cl cotransporter is stimulated by the ischemic factors hypoxia, aglycemia, and arginine vasopressin (AVP), and that inhibition of the cotransporter by intravenous bumetanide greatly reduces edema and infarct in rats subjected to permanent middle cerebral artery occlusion (pMCAO). More recently, we showed that BBB Na/H exchanger activity is also stimulated by hypoxia, aglycemia, and AVP. The present study was conducted to further investigate the possibility that a BBB Na/H exchanger also participates in edema formation during ischemic stroke. Sprague-Dawley rats were subjected to pMCAO and then brain edema and Na content assessed by magnetic resonance imaging diffusion-weighed imaging and magnetic resonance spectroscopy Na spectroscopy, respectively, for up to 210 minutes. We found that intravenous administration of the specific Na/H exchange inhibitor HOE-642 significantly decreased brain Na uptake and reduced cerebral edema, brain swelling, and infarct volume. These findings support the hypothesis that edema formation and brain Na uptake during the early hours of cerebral ischemia involve BBB Na/H exchanger activity as well as Na–K–Cl cotransporter activity.

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Blood brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema during ischemic stroke

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.695.13 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Yi-Je (Jay) Chen ◽

Natalie Yuen ◽

Breanna K Wallace ◽

Heike Wulff ◽

Martha E O'Donnell

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain ◽

Na Uptake

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NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in vitro and protects blood–brain barrier integrity in murine stroke

Cell Death and Disease ◽

10.1038/s41419-021-04379-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Maximilian Bellut ◽

Lena Papp ◽

Michael Bieber ◽

Peter Kraft ◽

Guido Stoll ◽

...

Keyword(s):

Blood Brain Barrier ◽

Nlrp3 Inflammasome ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Brain Barrier ◽

Edema Formation ◽

Pyrin Domain ◽

Volume Functional ◽

Blood Brain

AbstractIn ischemic stroke (IS) impairment of the blood–brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and—in good agreement with the in vitro results—MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.

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Abstract P335: Post-Treatment Blood-Brain Barrier Disruption is Associated With Cerebral Edema and Extends Into Penumbral Tissue in Anterior Circulation Large Vessel Occlusion

Stroke ◽

10.1161/str.52.suppl_1.p335 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Felix Ng ◽

Gagan Sharma ◽

Leonid Churilov ◽

Nawaf Yassi ◽

Timothy Kleinig ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Cerebral Edema ◽

Post Treatment ◽

Large Vessel ◽

Brain Barrier ◽

Large Vessel Occlusion ◽

Anterior Circulation ◽

Vessel Occlusion ◽

Blood Brain

Background: Blood Brain Barrier (BBB) disruption is central to vasogenic edema development after ischemia in preclinical studies. We investigated the relationship between BBB disruption and cerebral edema in patients receiving reperfusion therapies for anterior circulation large vessel occlusion. Methods: In a post-hoc pooled analysis of the Tenecteplase versus Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) part 1 and 2 multicenter RCTs, the DWI lesion on 24h post-treatment MRI and peri-infarct salvaged penumbra derived from pre-treatment CT-Perfusion (CTP) were segmented and registered to 24h MR Perfusion. A validated permeability measure (percentage of measured cerebral blood volume lost due to T1 effect from gadolinium leakage across the BBB) was calculated for each ROI. The association between post-treatment BBB disruption in the infarct and cerebral edema assessed on a trichotomized ordinal scale of negligible (<1mm midline shift), mild (≥1 to <5mm) or severe (≥5mm) was analyzed using ordinal logistic regression. Results: Of 220 patients analyzed, median (IQR) BBB disruption was 2.36(1.4-4.1)% in the infarct, 1.61(1.0-2.6)% in salvaged penumbra and 0.98(0.7-1.5)% in normal brain (p<0.001). There were 119 (54.1%) patients with negligible, 90 (40.8%) mild and 11 (5.0%) severe cerebral edema at 24h. In multivariable analysis, infarct BBB disruption was associated with increased cerebral edema (cOR=1.11 per%, 95%CI 1.02-1.21;p=0.012, adjusted for age, admission NIHSS and reperfusion (mTICI2b/3 or >50% reperfusion on early CTP 2h post-lysis). Infarct BBB disruption correlated with follow-up infarct volume (rho=0.37;p<0.001), and was associated with parenchymal hematoma (aOR=1.18, 95%CI 1.00-1.40;p=0.048) and worse outcome assessed on 90-day modified Rankin Scale (cOR=1.16 per%, 95%CI 1.08-1.26;p<0.001, adjusted for age, admission NIHSS and reperfusion). Conclusions: BBB disruption after reperfusion treatment extends beyond the infarct lesion, and is associated with cerebral edema development, hemorrhagic transformation and poor outcome. Further studies to evaluate BBB integrity as an imaging biomarker and potential therapeutic target in malignant cerebral edema after ischemic stroke are needed.

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