scholarly journals Contribution of Poly(ADP-Ribose) Polymerase to Postischemic Blood—Brain Barrier Damage in Rats

2007 ◽  
Vol 27 (7) ◽  
pp. 1318-1326 ◽  
Author(s):  
Gábor Lenzsér ◽  
Béla Kis ◽  
James A Snipes ◽  
Tamás Gáspár ◽  
Péter Sándor ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Significant Role ◽  
Ischemia Reperfusion ◽  
Brain Barrier ◽  
Parp Inhibition ◽  
Edema Formation ◽  
Arterial Blood ◽  
Blood Brain ◽  
Junction Protein ◽  
The Brain

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood–brain barrier (BBB) disruption and edema formation after ischemia–reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)- N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia–reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170 ± 9, saline: 760 ± 95, PJ34: 472 ± 61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction.

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

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.

scholarly journals Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations

2005 ◽  
Vol 289 (2) ◽  
pp. H738-H743 ◽  
Author(s):  
Tracy A. Brooks ◽  
Brian T. Hawkins ◽  
Jason D. Huber ◽  
Richard D. Egleton ◽  
Thomas P. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Pain ◽  
Brain Barrier ◽  
Sprague Dawley ◽  
Edema Formation ◽  
Chronic Inflammatory Pain ◽  
In Situ Perfusion ◽  
Blood Brain ◽  
Junction Protein ◽  
The Right

The blood-brain barrier (BBB) maintains brain homeostasis by limiting entry of substances to the central nervous system through interaction of transmembrane and intracellular proteins that make up endothelial cell tight junctions (TJs). Recently it was shown that the BBB can be modulated by disease pathologies including inflammatory pain. This study examined the effects of chronic inflammatory pain on the functional and molecular integrity of the BBB. Inflammatory pain was induced by injection of complete Freund's adjuvant (CFA) into the right plantar hindpaw in female Sprague-Dawley rats under halothane anesthesia; control animals were injected with saline. Edema and hyperalgesia were assessed by plethysmography and infrared paw-withdrawal latency. At 72 h postinjection, significant edema formation and hyperalgesia were noted in the CFA-treated rats. Examination of permeability of the BBB by in situ perfusion of [14C]sucrose while rats were under pentobarbital anesthesia demonstrated that CFA treatment significantly increased brain sucrose uptake. Western blot analysis of BBB TJ proteins showed no change in expression of zonula occludens-1 (an accessory protein) or actin (a cytoskeletal protein) with CFA treatment. Expression of the transmembrane TJ proteins occludin and claudin-3 and -5 significantly changed with CFA treatment with a 60% decrease in occludin, a 450% increase in claudin-3, and a 615% increase in claudin-5 expression. This study demonstrates that during chronic inflammatory pain, alterations in BBB function are associated with changes in specific transmembrane TJ proteins.

Effects of selective hypothermia on blood-brain barrier integrity and tight junction protein expression levels after intracerebral hemorrhage in rats

2013 ◽  
Vol 394 (10) ◽  
pp. 1317-1324 ◽  
Author(s):  
Hongwei Sun ◽  
Ying Tang ◽  
Xiqin Guan ◽  
Lanfeng Li ◽  
Desheng Wang
Keyword(s):  
Intracerebral Hemorrhage ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Edema Formation ◽  
Expression Levels ◽  
Blood Brain ◽  
Tnf Α ◽  
Junction Protein ◽  
Local Hypothermia

Abstract Hypothermia has neuroprotective effects on global cerebral ischemic injuries. However, its efficacy after intracerebral hemorrhage (ICH) is inconclusive. In this study, bacterial collagenase was used to induce ICH stroke in male Wistar rats. We assessed the effects of normothermia and 4 h of local hypothermia (∼33.2°C) initiated 1, 6, or 12 h after collagenase infusion on hemorrhage volume and neurological outcomes. Following early cooling initiated after 1 h, blood-brain barrier (BBB) disruption and brain water content were tested. Furthermore, the expression levels of tight junction (TJ) proteins (claudin 5 and occludin) and the proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were determined using Western blotting, real-time quantitative PCR, and immunohistochemical staining at 1 and 3 d after ICH. Early local hypothermia tends to reduce hemorrhagic volume and neurological deficits, but the difference is not statistically significant compared with other groups. However, early hypothermia significantly reduces BBB disruption, edema formation, the expression levels of IL-1β and TNF-α, and the loss of TJ proteins. Together, these data suggest that local hypothermia is an effective treatment for edema formation and BBB disruption via the upregulation of TJ proteins and the suppression of TNF-α and IL-1β.

scholarly journals Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

2020 ◽  
Author(s):  
Benjamin P. Heithoff ◽  
Kijana K. George ◽  
Aubrey N. Phares ◽  
Ivan A. Zuidhoek ◽  
Carmen Munoz-Ballester ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Glucose Transporter ◽  
Morphological Changes ◽  
Cell Types ◽  
Adult Brain ◽  
Brain Barrier ◽  
Glucose Transporter 1 ◽  
Blood Brain ◽  
Junction Protein ◽  
The Brain

AbstractIn the adult brain, multiple cell types are known to produce factors that regulate blood-brain barrier properties, including astrocytes. Yet several recent studies disputed a role for mature astrocytes at the blood-brain barrier. To determine if astrocytes contribute a non-redundant and necessary function in maintaining the adult blood-brain barrier, we used a mouse model of tamoxifen-inducible astrocyte ablation. In adult mice, tamoxifen induction caused sparse apoptotic astrocyte cell death within 2 hours. Indicative of BBB damage, leakage of the small molecule Cadaverine and the large plasma protein fibrinogen into the brain parenchyma indicative of BBB damage was detected as early as astrocyte ablation was present. Vessels within and close to regions of astrocyte loss had lower expression of the tight junction protein zonula occludens-1 while endothelial glucose transporter 1 expression was undisturbed. Cadaverine leakage persisted for several weeks suggesting a lack of barrier repair. This is consistent with the finding that ablated astrocytes were not replaced. Adjacent astrocytes responded with partial non-proliferative astrogliosis, characterized by morphological changes and delayed phosphorylation of STAT3, which restricted dye leakage to the brain and vessel surface areas lacking coverage by astrocytes one month after ablation. In conclusion, astrocytes are necessary to maintain blood-brain barrier integrity in the adult brain. Blood-brain barrier-regulating factors secreted by other cell types, such as pericytes, are not sufficient to compensate for astrocyte loss.Main PointsMature astrocytes are necessary for maintenance of endothelial tight junctions in the adult brain. Ablated astrocytes are not replaced by proliferation or process extension of neighboring astrocytes resulting in long-term blood-brain barrier damage.

scholarly journals Cerebral Ischemia–Reperfusion Injury in Rats—A 3 T MRI Study on Biphasic Blood–Brain Barrier Opening and the Dynamics of Edema Formation

2009 ◽  
Vol 29 (11) ◽  
pp. 1846-1855 ◽  
Author(s):  
Deepu R Pillai ◽  
Michael S Dittmar ◽  
Dobri Baldaranov ◽  
Robin M Heidemann ◽  
Erica C Henning ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ischemia Reperfusion Injury ◽  
Vasogenic Edema ◽  
Ischemia Reperfusion ◽  
Brain Barrier ◽  
Edema Formation ◽  
Temporal Shift ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Bbb Opening

Serial magnetic resonance imaging (MRI) was performed to investigate the temporal and spatial relationship between the biphasic nature of blood–brain barrier (BBB) opening and, in parallel, edema formation after ischemia–reperfusion (I/R) injury in rats. T2-weighted imaging combined with T2-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T1-weighted imaging was performed before and after gadolinium contrast at the last three time points to assess BBB integrity. The biphasic course of BBB opening with a significant reduction in BBB permeability at 24 h after reperfusion, associated with a progressive expansion of leaky BBB volume, was accompanied by a peak ipsilateral edema formation. In addition, at 4 h after reperfusion, edema formation could also be detected at the contralateral striatum as determined by the elevated T2-values that persisted to varying degrees, indicative of widespread effects of I/R injury. The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation. Stroke therapy aimed at vasogenic edema and drug delivery for neuroprotection may also be guided according to the functional status of the BBB, and these findings have to be confirmed in human stroke.

scholarly journals Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after λ-carrageenan-induced inflammatory pain

2006 ◽  
Vol 290 (2) ◽  
pp. H732-H740 ◽  
Author(s):  
J. D. Huber ◽  
C. R. Campos ◽  
K. S. Mark ◽  
T. P. Davis
Keyword(s):  
Protein Expression ◽  
Blood Brain Barrier ◽  
Proinflammatory Cytokines ◽  
Inflammatory Pain ◽  
Microglial Activation ◽  
Brain Barrier ◽  
Cell Counts ◽  
Blood Brain ◽  
Junction Protein ◽  
The Brain

Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability and altered tight junction protein expression and the delivery of opioid analgesics to the brain. What remains unknown is which pathways and mediators during peripheral inflammation affect BBB function and structure. The current study investigated effects of λ-carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of proinflammatory cytokines and microglial activation in the brain to elucidate pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels after CIP using RT-PCR and Western blot analyses, screened inflammatory cytokines during the time course of inflammation, assessed white blood cell counts, and probed for BBB and central nervous system stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression after CIP with no change in circulating levels of several proinflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed that the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal and parietal cortices, which directly correlated with increased expression of activated microglia. The findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic proinflammatory mediators play no apparent role in the early response (1–6 h); however, brain region-specific increases in microglial activation suggest a potential for a central-mediated response.

scholarly journals Deletion of Astroglial Connexins Weakens the Blood–Brain Barrier

2012 ◽  
Vol 32 (8) ◽  
pp. 1457-1467 ◽  
Author(s):  
Pascal Ezan ◽  
Pascal André ◽  
Salvatore Cisternino ◽  
Bruno Saubaméa ◽  
Anne-Cécile Boulay ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Vascular System ◽  
Water Channel ◽  
Brain Barrier ◽  
Partial Loss ◽  
Blood Brain ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
The Brain ◽  
Astrocyte Endfeet

Astrocytes, the most prominent glial cell type in the brain, send specialized processes named endfeet, which enwrap blood vessels and express a large molecular repertoire dedicated to the physiology of the vascular system. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein connexins 43 and 30 (Cx43 and Cx30) allowing for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. The contribution of astroglial connexins to the physiology of the brain vascular system has never been addressed. Here, we show that Cx43 and Cx30 expression at the level of perivascular endfeet starts from postnatal days 2 and 12 and is fully mature at postnatal days 15 and 20, respectively, indicating that astroglial perivascular connectivity occurs and develops during postnatal blood–brain barrier (BBB) maturation. We demonstrate that mice lacking Cx30 and Cx43 in GFAP (glial fibrillary acidic protein)-positive cells display astrocyte endfeet edema and a partial loss of the astroglial water channel aquaporin-4 and β-dystroglycan, a transmembrane receptor anchoring astrocyte endfeet to the perivascular basal lamina. Furthermore, the absence of astroglial connexins weakens the BBB, which opens upon increased hydrostatic vascular pressure and shear stress. These results demonstrate that astroglial connexins are necessary to maintain BBB integrity.

scholarly journals miR-98 reduces endothelial dysfunction by protecting blood–brain barrier (BBB) and improves neurological outcomes in mouse ischemia/reperfusion stroke model

2019 ◽  
Vol 40 (10) ◽  
pp. 1953-1965 ◽  
Author(s):  
David L Bernstein ◽  
Viviana Zuluaga-Ramirez ◽  
Sachin Gajghate ◽  
Nancy L Reichenbach ◽  
Boris Polyak ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Inflammatory Factors ◽  
Brain Endothelium ◽  
Blood Brain ◽  
The Brain

Most neurological diseases, including stroke, lead to some degree of blood–brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs’ role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, both in vivo and in vitro, transient middle cerebral artery occlusion (tMCAO), and oxygen–glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse’s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6CHI leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetration in vivo and improved transendothelial electrical resistance (TEER) in vitro. Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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