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Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide.

ABSTRACT: The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood-brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3-6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents.

SUBMITTER: On NH

PROVIDER: S-EPMC3993937 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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C-type natriuretic peptide modulates permeability of the blood-brain barrier.

Project description:C-type natriuretic peptide (CNP) is abundant in brain and is reported to exert autocrine function in vascular cells, but its effect on blood-brain barrier (BBB) permeability has not been clarified yet. Here, we examined this effect. Transendothelial electrical resistance (TEER) of in vitro BBB model, composed of bovine brain microvascular endothelial cells and astrocytes, was significantly dose dependently decreased by CNP (1, 10, and 100 nmol/L). C-type natriuretic peptide treatment reduced both the messenger RNA (mRNA) and protein expressions of tight junction (TJ) protein zonula occludens-1 (ZO-1). The effects on TEER, mRNA, and protein expressions of ZO-1 were mimicked by cyclic GMP (cGMP) analog 8-bromo-cGMP (1 ?mol/L) and reversed by protein kinase G (PKG) inhibitor Rp-8-CPT-cGMPS (100 ?mol/L), thus implying the role of PKG and cGMP signaling in BBB function. Transcription factor JunD knockdown by small interfering RNA resulted in no change of permeability by CNP. In vivo study of mouse brain by fluorimetric analysis with intravenous administration of sodium fluorescein (40 mg/kg) also showed a significant increase in BBB permeability by CNP (10 nmol/kg, intravenously). These findings suggest that CNP modulates the BBB permeability by altering ZO-1 expression.

| S-EPMC3982079 | biostudies-literature

The gut microbiota influences blood-brain barrier permeability in mice.

Project description:Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.

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Modulation of Blood-Brain Barrier Permeability by Activating Adenosine A2 Receptors in Oncological Treatment.

Project description:The blood-brain barrier (BBB) plays an important protective role in the central nervous system and maintains its homeostasis. It regulates transport into brain tissue and protects neurons against the toxic effects of substances circulating in the blood. However, in the case of neurological diseases or primary brain tumors, i.e., gliomas, the higher permeability of the blood-derived substances in the brain tissue is necessary. Currently applied methods of treatment for the primary brain neoplasms include surgical removal of the tumor, radiation therapy, and chemotherapy. Despite the abovementioned treatment methods, the prognosis of primary brain tumors remains bad. Moreover, chemotherapy options seem to be limited due to low drug penetration into the cancerous tissue. Modulation of the blood-brain barrier permeability may contribute to an increase in the concentration of the drug in the CNS and thus increase the effectiveness of therapy. Interestingly, endothelial cells in cerebral vessels are characterized by the presence of adenosine 2A receptors (A2AR). It has been shown that substances affecting these receptors regulate the permeability of the BBB. The mechanism of increasing the BBB permeability by A2AR agonists is the actin-cytoskeletal reorganization and acting on the tight junctions. In this case, the A2AR seems to be a promising therapy target. This article aims to assess the possibility of increasing the BBB permeability through A2AR agonists to increase the effectiveness of chemotherapy and to improve the results of cancer therapy.

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Computational prediction of blood-brain barrier permeability using decision tree induction.

Project description:Predicting blood-brain barrier (BBB) permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS) values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK) was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction) on both descriptor sets. Models with a corrected classification rate (CCR) of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO)-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP) and charge (polar surface area), which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component.

| S-EPMC6269008 | biostudies-other

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT).

Project description:The blood-brain barrier (BBB) is a major obstacle in drug delivery for diseases of the brain, and today there is no standardized route to surpass it. One technique to locally and transiently disrupt the BBB, is focused ultrasound in combination with gas-filled microbubbles. However, the microbubbles used are typically developed for ultrasound imaging, not BBB disruption. Here we describe efficient opening of the BBB using the promising novel Acoustic Cluster Therapy (ACT), that recently has been used in combination with Abraxane® to successfully treat subcutaneous tumors of human prostate adenocarcinoma in mice. ACT is based on the conjugation of microbubbles to liquid oil microdroplets through electrostatic interactions. Upon activation in an ultrasound field, the microdroplet phase transfers to form a larger bubble that transiently lodges in the microvasculature. Further insonation induces volume oscillations of the activated bubble, which in turn induce biomechanical effects that increase the permeability of the BBB. ACT was able to safely and temporarily permeabilize the BBB, using an acoustic power 5-10 times lower than applied for conventional microbubbles, and successfully deliver small and large molecules into the brain.

| S-EPMC5196882 | biostudies-literature

Pharmacological Modulation of Blood-Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions.

Project description:The blood-brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

| S-EPMC7650794 | biostudies-literature

Blood-brain barrier permeability and tPA-mediated neurotoxicity.

Project description:Tissue type plasminogen activator (tPA) can induce neuronal apoptosis, disrupt the blood-brain barrier (BBB), and promote dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process that is associated with reversible neurotoxicity, brain damage, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as in thromboembolic models of stroke.

| S-EPMC4423729 | biostudies-literature

Blood-brain barrier permeability analysis of plant ceramides.

Project description:Ceramides, a type of sphingolipid, are cell membrane components and lipid mediators that modulate a variety of cell functions. In plants, ceramides are mostly present in a glucosylated glucosylceramide (GlcCer) form. We previously showed that oral administration of konjac-derived GlcCer to a mouse model of Alzheimer's disease reduced brain amyloid-β and amyloid plaques. Dietary plant GlcCer compounds are absorbed as ceramides, but it is unclear whether they can cross the blood-brain barrier (BBB). Herein, we evaluated the BBB permeability of synthetic plant-type ceramides (4, 8-sphingadienine, d18:2) using mouse and BBB cell culture models, and found that they could permeate the BBB both in vivo and in vitro. In addition, administrated ceramides were partially metabolized to other sphingolipid species, namely sphingomyelin (SM) and GlcCer, while crossing the BBB. Thus, plant ceramides can cross the BBB, suggesting that ceramides and their metabolites might affect brain functions.

| S-EPMC7605672 | biostudies-literature

Effects of centrifugation and whole-body vibrations on blood-brain barrier permeability in mice.

Project description:Modifications of gravity levels induce generalized adaptation of mammalian physiology, including vascular, brain, muscle, bone and immunity functions. As a crucial interface between the vascular system and the brain, the blood-brain barrier (BBB) acts as a filter to protect neurons from pathogens and inflammation. Here we compare the effects of several protocols of hypergravity induced by centrifugation and whole-body vibrations (WBV) on BBB integrity. The immunohistochemistry revealed immunoglobulin G (IgG) extravasation from blood to hippocampal parenchyma of mice centrifuged at 2 × g during 1 or 50 days, whereas short exposures to higher hypergravity mimicking the profiles of spaceflight landing and take-off (short exposures to 5 × g) had no effects. These results suggest prolonged centrifugation (>1 days) at 2 × g induced a BBB leakage. Moreover, WBV were similarly tested. The short exposure to +2 × g vibrations (900 s/day at 90 Hz) repeated for 63 days induced IgG extravasation in hippocampal parenchyma, whereas the progressive increase of vibrations from +0.5 to +2 × g for 63 days was not able to affect the IgG crossing through the BBB. Overall, these results suggest that the BBB permeability is sensitive to prolonged external accelerations. In conclusion, we advise that the protocols of WBV and centrifugation, proposed as countermeasure to spaceflight, should be designed with progressively increasing exposure to reduce potential side effects on the BBB.

| S-EPMC6946672 | biostudies-literature

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