Blood-central Nervous System Barriers Research Articles

Bacteria elevate extracellular adenosine to exploit host signaling for blood-brain barrier disruption

ABSTRACT Bacterial meningitis remains a substantial cause of mortality worldwide and survivors may have severe lifelong disability. Although we know that meningeal bacterial pathogens must cross blood-central nervous system (CNS) barriers, the mechanisms which facilitate the virulence of these pathogens are poorly understood. Here, we show that adenosine from a surface enzyme (Ssads) of Streptococcus suis facilitates this pathogen’s entry into mouse brains. Monolayer translocation assays (from the human cerebrovascular endothelium) and experiments using diverse inhibitors and agonists together demonstrate that activation of the A1 adenosine receptor signaling cascade in hosts, as well as attendant cytoskeleton remodeling, promote S. suis penetration across blood-CNS barriers. Importantly, our additional findings showing that Ssads orthologs from other bacterial species also promote their translocation across barriers suggest that exploitation of A1 AR signaling may be a general mechanism of bacterial virulence.

ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases. The family of ATP-binding cassette (ABC) transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers. These efflux transporters include P-glycoprotein (abcb1), ‘breast cancer resistance protein’ (abcg2) and the various ‘multidrug resistance-associated proteins’ (abccs). Understanding which efflux transporters are present at the blood-spinal cord, blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue. Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age, disease and environmental challenge. This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist. In the present review, the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on: (i) protecting the spinal cord from adverse effects of systemically directed drugs, and (ii) limiting centrally directed drugs from accessing their active sites within the spinal cord.

Gradual Suppression of Transcytosis Governs Functional Blood-Retinal Barrier Formation

Blood-central nervous system (CNS) barriers partition neural tissues from the blood, providing a homeostatic environment for proper neural function. The endothelial cells that form blood-CNS barriers have specialized tight junctions and low rates of transcytosis to limit the flux of substances between blood and CNS. However, the relative contributions of these properties to CNS barrier permeability are unknown. Here, by studying functional blood-retinal barrier (BRB) formation in mice, we found that immature vessel leakage occurs entirely through transcytosis, as specialized tight junctions are functional as early as vessel entry into the CNS. A functional barrier forms only when transcytosis is gradually suppressed during development. Mutant mice with elevated or reduced levels of transcytosis have delayed or precocious sealing of the BRB, respectively. Therefore, the temporal regulation of transcytosis governs the development of a functional BRB, and suppression of transcytosis is a principal contributor for functional barrier formation.

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment.

Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.

Glioblastoma Multiforme and Lipid Nanocapsules: A Review.

Epidemiological data on central nervous system disorders call for a focus on the major hindrance to brain drug delivery, blood-central nervous system barriers. Otherwise, there is little chance of improving the short-term survival of patients with diseases such as glioblastoma multiforme, which is one of the brain disorders associated with many years of life lost. Targetable nanocarriers for treating malignant gliomas are a unique way to overcome low chemotherapeutic levels at target sites devoid of systemic toxicity. This review describes the currently available targetable nanocarriers, focusing particularly on one of the newest nanocarriers, lipid nanocapsules. All of the strategies that are likely to be exploited by lipid nanocapsules to bypass blood-central nervous system barriers, including the most recent targeting approaches (mesenchymal cells), and novel administration routes (convection enhanced delivery) are discussed, together with their most remarkable achievements in glioma-implanted animal models. Although these systems are promising, much research remains to be done in this field.

Effects of Peripheral Inflammation on the Blood-Spinal Cord Barrier

BackgroundChanges in the blood-central nervous system barriers occur under pathological conditions including inflammation and contribute to central manifestations of various diseases. After short-lasting peripheral and neurogenic inflammation, the evidence is mixed whether there are consistent blood-spinal cord changes. In the current study, we examine changes in the blood-spinal cord barrier after intraplantar capsaicin and λ-carrageenan using several methods: changes in occludin protein, immunoglobulin G accumulation, and fluorescent dye penetration. We also examine potential sex differences in male and female adult rats.ResultsAfter peripheral carrageenan inflammation, but not capsaicin inflammation, immunohistochemistry shows occludin protein in lumbar spinal cord to be significantly altered at 72 hours post-injection. In addition, there is also significant immunoglobulin G detected in lumbar and thoracic spinal cord at this timepoint in both male and female rats. However, acute administration of sodium fluorescein or Evans Blue dyes is not detected in the parenchyma at this timepoint.ConclusionsOur results show that carrageenan inflammation induces changes in tight junction protein and immunoglobulin G accumulation, but these may not be indicative of a blood-spinal cord barrier breakdown. These changes appear transiently after peak nociception and may be indicative of reversible pathology that resolves together with inflammation.

The Blood-Central Nervous System Barriers Actively Control Immune Cell Entry into the Central Nervous System

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Relation between the increase in the diffusional permeability of the blood-central nervous system barrier and other changes during the development of experimental allergic encephalomyelitis in the lewis rat

The reduction in the effectiveness of the blood-brain and blood-spinal cord barriers, previously seen in rats at the height of the acute episode of experimental allergic encephalomyelitis, has now been measured at various stages in the development of the disease up to 60 days after inoculation with guinea pig spinal cord in complete Freund's adjuvants. The marker of extracellular space, radioactively labelled mannitol, only crosses the blood-central nervous system barriers very slowly by passive diffusion in normal rats. An abnormal penetration of this marker into the central nervous system began to develop during the second week after inoculation, appearing first in the lower spinal cord, where it also reaches the highest level during the acute phase of the attack. The leak begins before either the clinical signs become evident or cuffing is seen around blood vessels in stained sections. As the clinical signs are disappearing, from about 15 days onwards, the permeability of the barrier returns steadily to its normal low value, starting in the spinal cord, especially the caudal part. The timing of the reduction in the effectiveness of the blood-central nervous system barrier in relation to other clinical and histological changes suggests that it may play a part in the development of the lesion. The relation between the timing of these changes in EAE and that in the development of a new lesion in (exacerbation of) multiple sclerosis is discussed.