Blood-cerebrospinal Fluid Barrier Permeability Research Articles

Chinese Bayberry Extract Regulates the Permeability of Blood-cerebrospinal Fluid Barrier and Ameliorates Experimental Colitis-Related Brain Comorbidities in Mice

Abstract Objectives The anxiety, depression symptoms, and cognitive decline related to inflammatory bowel disease (IBD) are recognized to have an impact on patients’ health. The blood-cerebrospinal fluid barrier (BCSFB) is important in somatic disease-related psychiatric and cognitive disorders, however, few treatments show efficacy. The objective of this research was to seek the protective effect of Chinese bayberry extract on inflammatory bowel disease-related brain comorbidities. Materials and Methods C57BL/6J mice were induced with dextran sulfate sodium (DSS) solution to establish the experimental model, followed by the administration of Chinese bayberry extract. Oxidative stress indexes, immunofluorescence of choroid plexus, and BCSFB permeability were further investigated. Results Chinese bayberry extract improved behavioral markers and reduced the level of oxidative stress in the brain. In addition, administration of the bayberry extract increased the tight junction proteins in the choroid plexus and a significant decrease in the permeability of the BCSFB. Conclusions Chinese bayberry extract has the potential therapeutic effect of relieving inflammatory bowel disease-related brain comorbidities. The underlying mechanism is associated with a decrease in oxidative stress in the brain and a decrease in the permeability of the BCSFB.

Blood-cerebrospinal fluid barrier permeability of metals/metalloids and its determinants in pediatric patients

Concerns regarding adverse effects of metal/metalloids exposure on brain development and neurological disorders among children are increasing. However, the transport patterns of metals/metalloids across the blood-cerebrospinal fluid barrier (BCSFB) need to be clarified in children. A total of 99 Chinese pediatric patients were enrolled from February 2020 to August 2021, with a median age of 6.76 months. We detected 16 metal/metalloid levels in matched serum and cerebrospinal fluid (CSF) samples using inductively coupled plasma mass spectrometry. The BCSFB permeability of metals/metalloids were estimated and the potential effects of biomedical parameters were explored. Most metals/metalloids were detectable among > 80.0% of CSF samples. Significant correlations were observed between strontium (Sr, r = 0.46), molybdenum (Mo, r = 0.50), and cadmium (Cd, r = 0.24) concentrations in serum and CSF (P < 0.05). Ratios of metal/metalloid levels in CSF to serum (Rmetal) ranged from 0.02 to 0.74, and hazardous metals/metalloids including arsenic (As), Cd, lead (Pb), thallium (Tl), and manganese (Mn) showed high transfer efficiencies across the BCSFB (Rmetals > 0.5). With the adjustment of age and sex, albumin, β2-microglobulin, and total protein levels in CSF were positively associated with copper (Cu) permeability (FDR-adjusted P < 0.05), while glucose in CSF was negatively correlated with calcium (Ca), Cu, Sr, and Mo BCSFB permeability (FDR-adjusted P < 0.05). Q-Alb promoted Cu permeability across the BCSFB (FDR-adjusted P < 0.001), while C-reactive protein levels in serum were positively associated with selenium (Se) permeability (FDR-adjusted P = 0.046). For the first time, our findings provided data for the BCSFB permeability of 16 metals/metalloids in children, and indicated that some biomedical parameters could influence the transformation of metals/metalloids from serum to CSF. Metals/metalloids with strong BCSFB permeability warrant attention for their potential neurotoxicity.

Pb induces ferroptosis in choroid plexus epithelial cells via Fe metabolism

Pb can enhance blood-cerebrospinal fluid barrier (BCSFB) permeability and accumulate in brain tissue, leading to central nervous system (CNS) dysfunction. Choroid plexus (CP) epithelial cells are the main components of the BCSFB with crucial functions in BCSFB maintenance. However, the mechanism by which Pb exposure affects CP epithelial cells remains unclear. Here, ferroptosis was identified as the major programmed cell death modality by sophisticated high-throughput sequencing and biochemical investigations in primary cultured CP epithelial cells following Pb exposure. Bioinformatics analysis using the ferroptosis database revealed that 16 ferroptosis-related genes were differentially expressed in primary cultured CP epithelial cells following Pb exposure. Among them, Gpx4, Slc7a11, Tfrc, and Slc40a1 were hub ferroptosis-related genes. In addition, CP epithelial cells can be impaired when the concentration of the Pb2+ reached 2050 μg/L (10 μM PbAc), which included the decrease of cell viability, Gpx4 and Slc7a11 proteins expression, etc. Moreover, inhibition of ferroptosis enhanced CP epithelial cell viability and reduced BCSFB permeability in vitro following Pb exposure. In summary, ferroptosis of CP epithelial cells is involved in BCSFB dysfunction following Pb exposure. Gpx4, Slc7a11, Tfrc, and Slc40a1 are hub ferroptosis-related genes in CP epithelial cells.

Blood-CSF-barrier permeability in tuberculous meningitis and its association with clinical, MRI and inflammatory cytokines

Blood -cerebrospinal fluid-barrier (BCB) disruption in tuberculous meningitis (TBM) may be mediated by inflammatory cytokines, and may determine clinico-radiological severity and outcome. We report BCB permeability in TBM and its relationship with inflammatory cytokines (TNF-α, IL-1β and IL-6), clinical severity, MRI changes and outcome. 55 TBM patients with a median age of 26 years were included. Their clinical, cerebrospinal fluid (CSF) and MRI findings were noted. The severity of meningitis was graded into stages I to III. Cranial MRI was done, and the presence of exudates, granuloma, hydrocephalus and infarctions was noted. BCB permeability was assessed by a ratio of CSF albumin to serum albumin (Qalb). The concentration of TNF-α, IL-1β and IL-6 in CSF were measured by cytokine bead array. The Qalb in the patients was more than the mean + 2.5 SD of controls. In TBM, Qalb correlated with TNF- α (r = 0.47; p = 0.01), CSF cells (r = 0.29; p = 0.02) and exudate on MRI (0.18 ± 0.009 Vs 0.13 ± 0.008; p = 0.04). There was however no association of Qalb with demographic variables, stage, tuberculoma, infarction and hydrocephalus. At 6 months, 11(20%) died, 10(18.2%) had poor and 34(61.8%) had a good recovery.BCB permeability in TBM correlated with TNF-α, CSF pleocytosis and exudates but not with severity of meningitis and outcome.

Exposure and Blood–Cerebrospinal Fluid Barrier Permeability of PFASs in Neonates

Exposure and Blood–Cerebrospinal Fluid Barrier Permeability of PFASs in Neonates

The adenosine A2Areceptor alleviates postoperative delirium‐like behaviors by restoring blood cerebrospinal barrier permeability in rats

Postoperative delirium (POD) is a common postoperative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood cerebrospinal fluid barrier (BCB) and brain blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2A R), a key regulator of the permeability of barriers, on surgery-induced increased permeability of BCB and POD-like behaviors. Open field, buried food and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2A R, GTP-RhoA and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC-dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO-1, occludin and claudin1) proteins, increased concentrations of NaFI and FITC-dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD-like behaviors in rats. An A2A R antagonist alleviated POD-like behaviors in rats. Furthermore, the A2A R antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho-associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD-like behaviors induced by A2A R activation. Moreover, fasudil also abolished the increased levels of GTP-RhoA/ROCK2, decreased levels of tight junction proteins and increased permeability of BCB caused by A2A R activation. Our findings demonstrate that A2A R might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2A R as a therapeutic target for POD.

Oxidative stress in the choroid plexus contributes to blood–cerebrospinal fluid barrier disruption during sepsis development

BackgroundThe choroid plexus (CP), main component of blood–cerebrospinal fluid barrier (BCSFB), protects the brain from peripheral inflammation similar to the blood–brain barrier. Thus, CP is considered a critical target site of oxidative damage, which in sepsis oxidative stress is likely to be a major step in the development of brain damage. Functional alterations in CP may be associated with sepsis-induced brain injury. However, there is no description on the mechanisms associated with BCSFB disruption during sepsis development. Materials and methodsTo test this hypothesis, we examined time-dependent oxidative stress markers in CP and permeability of BCSFB in rats submitted to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham surgery (control). We assessed albumin cerebrospinal fluid/plasma concentration quotient (Qalb), an index of BCSFB dysfunction and in CP samples, the oxidative damage in lipids, proteins, antioxidant enzymes and nitrite/nitrate (N/N) concentration in 12, 24 and 48 h after CLP. ResultsThe increase of BCSFB permeability is time-related to the increase of N/N concentration, oxidative damage to lipid and proteins, and decrease of antioxidant enzyme superoxide dismutase activity at 12 h in the CP; and decrease of catalase activity in 12 and 24 h. ConclusionsIn experimental sepsis the BCSFB dysfunction occurs and oxidative stress seems to be a major step in this dysfunction.

Blood-Cerebrospinal Fluid Barrier Gradients in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Inflammatory Cytokines and Chemokines.

Background: The pathophysiology underlying altered blood-cerebrospinal fluid barrier (BCSFB) function in Alzheimer's disease (AD) is unknown but may relate to endothelial cell activation and cytokine mediated inflammation.Methods: Cerebrospinal fluid (CSF) and peripheral blood were concurrently collected from cognitively healthy controls (N = 21) and patients with mild cognitive impairment (MCI) (N = 8) or AD (N = 11). The paired serum and CSF samples were assayed for a panel of cytokines, chemokines, and related trophic factors using multiplex ELISAs. Dominance analysis models were conducted to determine the relative importance of the inflammatory factors in relationship to BCSFB permeability, as measured by CSF/serum ratios for urea, creatinine, and albumin.Results: BCSFB disruption to urea, a small molecule distributed by passive diffusion, had a full model coefficient of determination (r2) = 0.35, and large standardized dominance weights (>0.1) for monocyte chemoattractant protein-1, interleukin (IL)-15, IL-1rα, and IL-2 in serum. BCSFB disruption to creatinine, a larger molecule governed by active transport, had a full model r2 = 0.78, and large standardized dominance weights for monocyte inhibitor protein-1b in CSF and tumor necrosis factor-α in serum. BCSFB disruption to albumin, a much larger molecule, had a full model r2 = 0.62, and large standardized dominance weights for IL-17a, interferon-gamma, IL-2, and VEGF in CSF, as well IL-4 in serum.Conclusions: Inflammatory proteins have been widely documented in the AD brain. The results of the current study suggest that changes in BCSFB function resulting in altered permeability and transport are related to expression of specific inflammatory proteins, and that the shifting distribution of these proteins from serum to CSF in AD and MCI is correlated with more severe perturbations in BCSFB function.

Choroid Plexus Blood-CSF Barrier: Major Player in Brain Disease Modeling and Neuromedicine

The choroid plexus (CP) of the blood-cerebrospinal fluid barrier (BCSFB) impacts CSF homeostasis, brain diseases, and neuromedical translation. CP executes neuroendocrine, excretory, and neuroimmune actions. BCSFB diversely manages brain-spinal cord fluid environments, giving rise to a wide pathophysiology spectrum. Newly-discovered choroidal phenomena include integration of circadian clock signals, immune interaction with gut microbiotica, and expression of receptors to taste CSF composition. BCSFB tight junctions and transcellular mechanisms differ from blood-brain barrier (BBB) counterparts, variably regulating pathogen and leukocyte access to the CSF-brain nexus. This review highlights microbial agents, substrates and autoantigens using CP epithelial membranes to penetrate CSF and periventricular regions. Lipopolysaccharide (LPS) is analyzed as a barrier-damaging agent and neuroinflammation promoter. Transducing LPS- and toll-like receptor activity produce CP-CSF cytokines in sickness behavior and virulent sepsis-associated encephalopathy. Agents/systems that counter oxidative activity such as matrix metalloproteinase 8 inhibitors and Nrf2 activators (bile acids and isothiocyanates) show promise as neural and CP protectants. One review theme emphasizes CP’s preponderant role in initiating central diseases, and their remediation. In view of BCSFB permeability alterations and epithelial transformation, we discuss systemic lupus erythematosus, N-methyl D-aspartate-associated autoencephalitis, helicobacter disruption of BCSFB, toll-like receptor 2 stimulation in CP (neuroinflammation), the CP gateway for trypanosomes, and APOE-linked cholesterol transport into CSF. Another section treats concurrent involvement of BCSFB-BBB alterations in helminthic meningitis, forebrain ischemia, acute hyperthermia, leptin resistance/obesity, diabetes mellitus, and Alzheimer-type neurodegeneration. Barrier impairment is analyzed by injury type, time course, therapeutic strategies, and translational neuromedicine principles. The restorative power of BCSFB-transported growth factors, hormones and medicinal agents is emphasized for strengthening CP-CSF homeostatic mechanisms in seizures, stroke and Parkinsonism. A worthy therapeutic aim is to attenuate CNS disorders triggered by BCSFB malfunction, using CSF-delivered therapeutic agents for promoting neural viability.

Gene expression and functional annotation of human choroid plexus epithelium failure in Alzheimer's disease.

BackgroundAlzheimer’s disease (AD) is the most common form of dementia. AD has a multifactorial disease etiology and is currently untreatable. Multiple genes and molecular mechanisms have been implicated in AD, including ß-amyloid deposition in the brain, neurofibrillary tangle accumulation of hyper-phosphorylated Tau, synaptic failure, oxidative stress and inflammation. Relatively little is known about the role of the blood-brain barriers, especially the blood-cerebrospinal fluid barrier (BCSFB), in AD. The BCSFB is involved in cerebrospinal fluid (CSF) production, maintenance of brain homeostasis and neurodegenerative disorders.ResultsUsing an Agilent platform with common reference design, we performed a large scale gene expression analysis and functional annotation of the Choroid Plexus Epithelium (CPE), which forms the BCSFB. We obtained 2 groups of freshly frozen Choroid Plexus (CP) of 7 human donor brains each, with and without AD: Braak stages (0–1) and (5–6). We cut CP cryo-sections and isolated RNA from cresyl-violet stained, laser dissected CPE cells. Gene expression results were analysed with T-tests (R) and the knowledge-database Ingenuity.We found statistically significantly altered gene expression data sets, biological functions, canonical pathways, molecular networks and functionalities in AD-affected CPE. We observed specific cellular changes due to increased oxidative stress, such as the unfolded protein response, E1F2 and NRF2 signalling and the protein ubiquitin pathway. Most likely, the AD-affected BCSFB barrier becomes more permeable due to downregulation of CLDN5. Finally, our data also predicted down regulation of the glutathione mediated detoxification pathway and the urea cycle in the AD CPE, which suggest that the CPE sink action may be impaired. Remarkably, the expression of a number of genes known to be involved in AD, such as APP, PSEN1, PSEN2, TTR and CLU is moderate to high and remains stable in both healthy and affected CPE. Literature labelling of our new functional molecular networks confirmed multiple previous (molecular) observations in the AD literature and revealed many new ones.ConclusionsWe conclude that CPE failure in AD exists. Combining our data with those of the literature, we propose the following chronological and overlapping chain of events: increased Aß burden on CPE; increased oxidative stress in CPE; despite continuous high expression of TTR: decreased capability of CPE to process amyloid; (pro-) inflammatory and growth factor signalling by CPE; intracellular ubiquitin involvement, remodelling of CPE tight junctions and, finally, cellular atrophy. Our data corroborates the hypothesis that increased BCSFB permeability, especially loss of selective CLDN5-mediated paracellular transport, altered CSF production and CPE sink action, as well as loss of CPE mediated macrophage recruitment contribute to the pathogenesis of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2159-z) contains supplementary material, which is available to authorized users.

Cerebroprotein Hydrolysate- New Paradigm in Management of Neurological Problems

Cerebroprotein Hydrosylate enhances neurogenesis, neuronal survival, provides neuromodulatory action, increases/ modulates neuronal plasticity and neuronal repair and has neuroimmunotrophic actions and thus has a unique neurotrophic activity [6]. Cerebroprotein hydrosylate helps in Neuronal differentiation and protection against ischaemic and neurotoxic lesions. It regulates and improves neuronal metabolism. It reduces excitotoxic damage, blocks over-activation of calcium dependent proteases, and scavenges free oxygen radicals. It has been found in animal studies that early intervention with cerebroprotein hydrosylate reduces blood-brain and blood-cerebrospinal fluid barrier permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits caused by traumatic brain injury [7]. It improved brain bioelectrical activity, i.e. reduced EEG ratio by increasing fast frequencies and reducing slow activities and also improves cognitive performance in tasks, evaluating attention and memory functions in post acute traumatic brain injury patients [8].

Mir-203-mediated tricellulin mediates lead-induced in vitro loss of blood–cerebrospinal fluid barrier (BCB) function

The blood–cerebrospinal fluid barrier (BCB) plays a critical role in the maintenance of optimal brain function. Tricellulin (TRIC), a protein localized at the tricellular contact sites of epithelial cells is involved in the formation of tight junctions in various epithelial barriers. However, little is known about its expression in the choroidal epithelial cells. It is well established that lead (Pb) exposure increases the leakage of the BCB. The purpose of this study is to investigate the expression and localization of TRIC in choroidal epithelial cells in vitro and whether altered TRIC expression mediates Pb-induced loss of barrier function. We found that TRIC protein and mRNA were expressed in choroidal epithelial cells in vitro and TRIC was localized at the tricellular contacts, colocalizing with occludin. Downregulation of TRIC by siRNA increased the BCB permeability corroborated by altered transendothelial electrical resistance (TEER) and FITC–dextran flux. Treatment with 10μM Pb reduced TRIC protein expression, but overexpression of TRIC alleviated the Pb-induced increase in BCB permeability. Bioinformatics analysis showed that mir-203 was a potential microRNA (miRNA) binding motif on TRIC 3′UTR, and that Pb exposure increased the expression of mir-203. Treatment with a mir-203 inhibitor increased TRIC protein expression and attenuated the Pb-induced BCB leakage. Our results establish that TRIC plays an important role in regulating BCB function.

TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport.

The diffusion of materials from systemic circulation to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). Choroid plexus epithelial cells (CPECs) of the brain ventricles constitute the BCSFB and regulate the infiltration of plasma proteins as well as immune cells into the interstitium of the CNS. The barrier function is altered in pathologic conditions. However, the regulatory mechanism of BCSFB is not fully understood. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a polymodally gated divalent cation channel that is highly expressed in CPECs. TRPV4 was localized broadly on the apical membrane in swine CPECs, in contrast with an intense ciliary localization found on other cell types. Treatment with the TRPV4-specific agonist, GSK1016790A (GSK; EC₅₀ 34 nM), induced a robust calcium influx and an immediate serine/threonine protein phosphorylation. The agonist treatment induced a marked decrease in the amount of filamentous actin and disintegrated the cell junctions in 10-20 minutes. In contrast, inhibition of the basal TRPV4 activity with the TRPV4-specific antagonist, HC067047 (HC; IC₅₀ 74 nM), reduced the basolateral-to-apical transport of α-2-macroglobulin (A2M). Overall, this study demonstrated a novel physiologic function of TRPV4 in the regulation of BCSFB permeability.

Fibronectin changes in eosinophilic meningitis with blood–CSF barrier disruption

Fibronectin, which is present at relatively low levels in healthy central nervous systems (CNS), shows increased levels in meningitis. In this study, fibronectin processing was correlated with the increased permeability of the blood–cerebrospinal fluid (CSF) barrier as well as with the formation of eosinophil infiltrates in angiostrongyliasis meningitis. The immunohistochemistry results show matrix metalloproteinase-9 (MMP-9) is localized in the choroid plexus epithelium. Coimmunoprecipitation demonstrated fibronectin strongly binds MMP-9. Furthermore, treatment with the MMP-9 inhibitor GM6001 significantly inhibited fibronectin processing, reduced the blood–CSF barrier permeability, and decreased the eosinophil counts. The decreased fibronectin processing in CSF implies decreased cellular invasion of the subarachnoid space across the blood–CSF barrier. Therefore, increased fibronectin processing may be associated with barrier disruption and participate in the extravasation and migration of eosinophils into the CNS during experimental parasitic infection.

Synthesis and Validation of a Hydroxypyrone-Based, Potent, and Specific Matrix Metalloproteinase-12 Inhibitor with Anti-Inflammatory Activity In Vitro and In Vivo.

A hydroxypyrone-based matrix metalloproteinase (MMP) inhibitor was synthesized and assayed for its inhibitory capacity towards a panel of ten different MMPs. The compound exhibited selective inhibition towards MMP-12. The effects of inhibition of MMP-12 on endotoxemia and inflammation-induced blood-cerebrospinal fluid barrier (BCSFB) disruption were assessed both in vitro and in vivo. Similar to MMP-12 deficient mice, inhibitor-treated mice displayed significantly lower lipopolysaccharide- (LPS-) induced lethality compared to vehicle treated controls. Following LPS injection Mmp-12 mRNA expression was massively upregulated in choroid plexus tissue and a concomitant increase in BCSFB permeability was observed, which was restricted in inhibitor-treated mice. Moreover, an LPS-induced decrease in tight junction permeability of primary choroid plexus epithelial cells was attenuated by inhibitor application in vitro. Taken together, this hydroxypyrone-based inhibitor is selective towards MMP-12 and displays anti-inflammatory activity in vitro and in vivo.

Evaluation of blood–brain barrier and blood–cerebrospinal fluid barrier permeability of 2-phenoxy-indan-1-one derivatives using in vitro cell models

2-Phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function would not affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40-54 μM. And we suggested that 5,6-dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp.

Effects of acrylamide on the permeability of blood cerebrospinal fluid barrier in rats

To explore the effects of acrylamide on the permeability of blood cerebrospinal fluid barrier (BCB) and tight junction protein ZO-1 of choroid plexus in rats and to provide a theoretical basis for explaining the mechanism of nerve injury induced by acrylamide. Thirty two male Sprague-Dawley rats were randomly divided into ACR and control groups. ACR group was exposed to 20 mg/kg ACR daily for 5 days a week by intraperitoneal injection (i.p.) for 4 weeks. Control group was exposed to normal saline. The neurobehavioral tests (including sensatory and motor functions) were performed every week. At the end of exposure, Evan blue (EB) and Sodium fluorescein (NaFI) content in rat CSF were detected for determining the BCB permeability, Real-time PCR was used to measure the expression levels of ZO-1 mRNA in the epithelium cells of choroid plexus, and laser scanning confocal microscope (LSCM) was utilized to observe the distribution of ZO-1 protein. Neurobehavioral tests showed that the tail-flick latencies of ACR group were 27.77% and 53.71% as long as control group in the 3rd week and 4th week, respectively (P < 0.05). The hind lamb splay distances of ACR group were 131.76% and 153.77% as long as control group in the 3rd week and 4th week, respectively (P < 0.05). Evan blue (EB) and Sodium fluorescein (NaFI) content of ACR group were significantly higher than those of control group (P < 0.05). In the 4th week, the expression level of ZO-1 mRNA in ACR group was 0.21 +/- 0.07, which was significantly lower than that (0.31 +/- 0.11) in control group (P < 0.05). In the 4th week, the ZO-1 protein expression level of choroid plexus in ACR group was significantly lower than that in control group (P < 0.05). Acrylamide could increased the BCB permeability of rats, which may be involved in the central nervous injury induced by ACR.

Tight junction proteins vary in the choroid plexus of ewes according to photoperiod

Sheep from temperate latitudes exhibit seasonal variations in many physiological functions such as reproduction, food intake, body weight, and pelage growth. Majority of seasonal changes are controlled by the annual photoperiodic cycle and melatonin secretion. For reproduction, the resulting key event is a modulation of the negative feedback of steroids on gonadotropin secretion. However, this seasonal effect could also depend on variable uptake of steroids by the brain. Seasonal regulation of food intake also involves numerous peripheral hormones, among which the protein hormone leptin informs the brain on the metabolic status of the animal. It has been shown previously that access of progesterone, estradiol and leptin to the cerebrospinal fluid (CSF) increases under long days. This physiological modulation of the passage of hormones to the brain could depend on regulation of the permeability of the blood–CSF barrier. This study therefore compared the tight junction proteins in the choroid plexus of ewes exposed to short days or long days. Levels of occludin, zonula occludens proteins (ZO) ZO-1 and ZO-2, afadin and cadherin were significantly higher during short days, but no statistical difference was observed for junctional adhesion molecule 1 (JAM-1), ZO-3 or claudins 1 and 5. These results are consistent with an increase in the blood–CSF barrier permeability during long days through a regulation of tight junctions and show that the permeability could depend upon physiological conditions such as photoperiodic status.

Cerebrospinal fluid secretory Ca 2+-dependent phospholipase A2 activity: A biomarker of blood–cerebrospinal fluid barrier permeability

The blood–brain barrier, the blood–cerebrospinal fluid barrier (BCB) and other specialized brain barriers are increasingly recognized as a major obstacle to the treatment of most brain disorders. The impairment of these barriers has been implicated in neuropathology of several diseases, such as autism, ischemia, multiple sclerosis and Alzheimer disease. This dual function of the blood–neural barriers points out the importance and need for the development of techniques that can evaluate the nature and level of their integrity. Here we report the discovery of CSF secretory Ca 2+-dependent phospholipase A2 (sPLA2) activity as a measure of BCB permeability. Lumbar CSF from BCB impaired ( n = 26), multiple sclerosis ( n = 18) and healthy control ( n = 32) cases was analyzed using both a newly developed continuous fluorescence assay for CSF sPLA2 activity and CSF/Serum albumin ratio ( Q Alb), the most common and established method to evaluate BCB permeability. While both measurements showed no significant differences between multiple sclerosis and age-matched normal healthy cases, they were highly correlated. Though the CSF sPLA2 activity and Q Alb had over 95% agreement, the former was found to be more sensitive than the latter in measuring low levels of BCB impairment.

Quantitative evaluation of blood–cerebrospinal fluid barrier permeability in the rat with experimental meningitis using magnetic resonance imaging

Disruption of the blood–brain barrier (BBB) and/or the blood–cerebrospinal fluid barrier (BCSFB) is thought to be one of the major pathophysiological consequences of meningitis and contributes to the development of adverse neurological outcomes. In order to clarify this hypothesis further, we sequentially quantified the permeability of these barriers with magnetic resonance imaging (MRI) contrast enhancement using gadolinium–diethylene triamine pentaacetic acid (Gd–DTPA) in rats with various experimentally-induced meningitis. Meningeal inflammation was elicited by an intracisternal injection of interleukin (IL)-1β, prostaglandin (PG) E 2, or lipopolysaccharide (LPS). Barrier permeability was calculated from the gadolinium-enhancement ratio (GER) in the subarachnoid space (SAS). The secretion of Gd–DTPA into the SAS was monitored by T1-weighted imaging after an intravenous injection of Gd–DTPA. As a significant linear correlation was observed between the GER and the standard solution, the concentration of the secreted Gd–DTPA were determined from the GER. The maximal intensity in SAS was detected at 5 min after Gd–DTPA administration and it declined gradually. Among the inflammatory agents, IL-1β was found to induce the most severe meningitis as determined from the GER. The concentration of Gd–DTPA in the SAS increased in a dose-dependent manner following IL-1β intracisternal injection. On the other hand, no significant changes in signal intensity of the brain parenchymal areas due to IL-1β injection were observed. The findings suggest that the permeability of the BCSFB can be evaluated quantitatively by calculating the GER. MRI with Gd–DTPA provides a useful method to monitor the change in the permeability to the brain barriers.