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 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 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.

221 Functional Modulation of the Blood Brain Barrier

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 260-260
Author(s):  
Geoffrey Stricsek ◽  
Michael J Lang ◽  
Ashwini Dayal Sharan ◽  
Robert H Rosenwasser ◽  
Lorraine Iacovitti
Keyword(s):  
Blood Brain Barrier ◽  
Femoral Vein ◽  
Brain Barrier ◽  
Uptake Ratio ◽  
Sprague Dawley ◽  
Blood Brain ◽  
Tissue Homogenates ◽  
Bbb Permeability ◽  
The Right ◽  
Stimulation Of

Abstract INTRODUCTION Delivery of therapeutic agents to the brain is constrained by the blood-brain barrier (BBB). Previous work (Yarnitsky) suggested BBB permeability was increased with stimulation of the sphenopalatine ganglion (SPG). However, their model looked at FITC-dextran signal in CSF superfusate, a reflection of epithelial tight junctions at the blood-CSF barrier, and quantified BBB permeability using Evans blue, a marker insufficient for this role (Saunders). METHODS Experiments were conducted in Sprague-Dawley rats using 70 kDa FITC-dextran as a marker to quantify BBB permeability. Once anesthetized, the right femoral vein was exposed and catheterized. Next, SPG fibers were exposed behind the right eye and an electrode was hooked around those fibers. Stimulation occurred in blocks of 90 seconds of “on” time at 5 volts and 10 Hz followed by 60 seconds of “off” time. Injection of 0.1 mL of a 100 mg/mL concentration of FITC coincided with each “on” stimulation cycle; a total of 1.0 mL was injected per animal. Control animals were not stimulated, but had the same injection protocol as test animals. 90 seconds after the final injection, a blood sample was collected and the cerebrovasculature was flushed. Each brain was removed, equally divided, and homogenized. Post-centrifugation supernatant from blood and tissue homogenates was analyzed using fluorescent spectrometry. FITC concentrations were calculated using known standards. An uptake ratio was calculated by dividing sample FITC concentration by blood FITC concentration. RESULTS >Data from 4 control animals and 4 test animals demonstrated a significantly greater uptake ratio in test brains compared with control brains (P = 0.001). A significantly increased uptake ratio was also observed in both right and left hemispheres of test animals compared with controls (right, P = 0.03; left, P = 0.01). CONCLUSION Stimulation of SPG fibers significantly increased BBB permeability in both cerebral hemispheres of test animals when compared with controls.

scholarly journals Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 2007-2014 ◽  
Author(s):  
Richard S. Beard ◽  
Jason J. Reynolds ◽  
Shawn E. Bearden
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Junction Protein ◽  
Brain Barrier Permeability

Abstract Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change in expression of the adherens junction protein VE-cadherin with Hcy treatment, but there was a significant decrease in the amount of β-catenin at the membrane. Moreover, Hcy caused nuclear translocation of β-catenin and attachment to the promoter for the tight junction protein claudin-5, with concomitant reduction in claudin-5 expression. Using a murine model of HHcy (cbs+/−), treatment for 2 weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of claudin-5 and blood-brain barrier permeability to both exogenous sodium fluorescein and endogenous IgG. Memantine had no effect on these parameters in wild-type littermates. The same results were obtained using an in vitro model with brain microvascular endothelial cells. These data provide the first evidence that the NMDAr is required for Hcy-mediated increases in blood-brain barrier permeability. Modulating cerebral microvascular NMDAr activity may present a novel therapeutic target in diseases associated with opening of the blood-brain barrier in HHcy, such as stroke and dementia.

Abstract TP256: Mouse Model of Uremic Cerebral Microbleeds

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Wei Ling Lau ◽  
Mary Tarbiat-Boldaji ◽  
Hayley Smalls ◽  
Ane Nunes ◽  
Javad Savoj ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Cerebral Microbleeds ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Increased Risk ◽  
Junction Protein ◽  
Blood Brain Barrier Integrity

Introduction: Cerebral microbleeds are more common in chronic kidney disease (CKD) and dialysis patients compared to the general population. Diminished kidney function alone appears to be a risk factor for microbleeds, independent of age and hypertension. Microbleed burden in CKD patients is associated with increased risk of future hemorrhagic stroke and with cognitive dysfunction. The mechanisms that drive uremic microbleed formation are unclear. Hypothesis: We hypothesized that CKD mice are predisposed to develop cerebral microhemorrhages (the pathologic substrate of microbleeds), and that a standardized inflammatory stimulus (lipopolysaccharide, LPS) will amplify microhemorrhage burden in CKD mice compared to non-CKD controls (CTL). We also hypothesized that uremia induces depletion of tight junction proteins, altering blood-brain barrier integrity and representing a potential mechanism of microbleed formation. Methods: Animal groups included CTL (n=3), CKD (n=3), CTL+LPS (n=5) and CKD+LPS (n=5). CKD induction in male C57BL/6 mice was achieved via nephrotoxic adenine diet x18 days. Two weeks following CKD induction, CKD and control mice were treated with LPS 1 mg/kg i.p. dosed at 0, 6 and 24 hours. Brains were harvested one week after LPS injections and 40-micron sections were stained using Prussian blue to identify microhemorrhages. Immunohistochemistry was performed for the blood-brain barrier tight junction protein claudin-5. Results: CKD mice had significantly elevated blood urea nitrogen, and tubulointerstitial fibrosis was present on kidney histology. Total number of microhemorrhages per brain was 2.3±1.5 (mean ± standard error of the mean) for CTL mice, 8.3±1.5 for CKD mice, 23.2±4.2 for CTL+LPS mice, and 27.6±6.2 for CKD+LPS mice (p<0.05 for CKD+LPS vs. CTL). Immunostaining showed decreased claudin-5 expression in CKD mice compared to CTL. Conclusions: We have generated a mouse model that will facilitate future mechanistic studies in the field of uremic microbleeds. Our initial findings suggest that CKD alters blood-brain barrier integrity and that inflammation amplifies development of microbleeds in CKD.

Blood-Brain Barrier Sodium Transport and Brain Edema Formation

1995 ◽  
pp. 159-168 ◽  
Author(s):  
A. Lorris Betz ◽  
Steven R. Ennis ◽  
Xiao-dan Ren ◽  
Gerald P. Schielke ◽  
Richard F. Keep
Keyword(s):  
Brain Edema ◽  
Blood Brain Barrier ◽  
Sodium Transport ◽  
Brain Barrier ◽  
Edema Formation ◽  
Blood Brain ◽  
Brain Edema Formation

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.

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