Fluid Barrier Permeability Research Articles

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.

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

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

Blood\u2013brain and blood\u2013cerebrospinal fluid barrier permeability in spontaneously hypertensive rats

BackgroundHypertension is an important risk factor for cerebrovascular disease, including stroke and dementia. Both in humans and animal models of hypertension, neuropathological features such as brain atrophy and oedema have been reported. We hypothesised that cerebrovascular damage resulting from chronic hypertension would manifest itself in a more permeable blood–brain barrier and blood–cerebrospinal fluid barrier. In addition, more leaky barriers could potentially contribute to an enhanced interstitial fluid and cerebrospinal fluid formation, which could, in turn, lead to an elevated intracranial pressure.MethodsTo study this, we monitored intracranial pressure and estimated the cerebrospinal fluid production rate in spontaneously hypertensive (SHR) and normotensive rats (Wistar Kyoto, WKY) at 10 months of age. Blood–brain barrier and blood–cerebrospinal fluid barrier integrity was determined by measuring the leakage of fluorescein from the circulation into the brain and cerebrospinal fluid compartment. Prior to sacrifice, a fluorescently labelled lectin was injected into the bloodstream to visualise the vasculature and subsequently study a number of specific vascular characteristics in six different brain regions.ResultsBlood and brain fluorescein levels were not different between the two strains. However, cerebrospinal fluid fluorescein levels were significantly lower in SHR. This could not be explained by a difference in cerebrospinal fluid turnover, as cerebrospinal fluid production rates were similar in SHR and WKY, but may relate to a larger ventricular volume in the hypertensive strain. Also, intracranial pressure was not different between SHR and WKY. Morphometric analysis of capillary volume fraction, number of branches, capillary diameter, and total length did not reveal differences between SHR and WKY.ConclusionIn conclusion, we found no evidence for blood–brain barrier or blood–cerebrospinal fluid barrier leakage to a small solute, fluorescein, in rats with established hypertension.

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].

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.

Cerebrolysin reduces blood‐cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat

Traumatic brain injuries (TBIs) induce profound breakdown of the blood-brain and blood-cerebrospinal fluid barriers (BCSFB), brain pathology/edema, and sensory-motor disturbances. Because neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and glial cell-derived neurotrophic factor (GDNF), are neuroprotective in models of brain and spinal cord injuries, we hypothesized that a combination of neurotrophic factors would enhance neuroprotective efficacy. In the present investigation, we examined the effects of Cerebrolysin, a mixture of different neurotrophic factors (Ebewe Neuro Pharma, Austria) on the brain pathology and functional outcome in a rat model of TBI. TBI was produced under Equithesin (3 mL/kg, i.p.) anesthesia by making a longitudinal incision into the right parietal cerebral cortex. Untreated injured rats developed profound disruption of the blood-brain barrier (BBB) to proteins, edema/cell injury, and marked sensory-motor dysfunctions on rota-rod and grid-walking tests at 5 h TBI. Intracerebroventricular administration of Cerebrolysin (10 or 30 microL) either 5 min or 1 h after TBI significantly reduced leakage of Evans blue and radioiodine tracers across the BBB and BCSFB, and attenuated brain edema formation/neuronal damage in the cortex as well as underlying subcortical regions. Cerebrolysin-treated animals also had improved sensory-motor functions. However, administration of Cerebrolysin 2 h after TBI did not affect these parameters significantly. These observations in TBI demonstrate that early intervention with Cerebrolysin reduces BBB and BCSFB permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits. Taken together, our observations suggest that Cerebrolysin has potential therapeutic value in TBI.

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.

Neuroinflammatory Role of Prostaglandins during Experimental Meningitis: Evidence Suggestive of an in Vivo Relationship between Nitric Oxide and Prostaglandins

Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during meningitis. The purpose of the present study was to pharmacologically inhibit cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the prostaglandin contribution to blood-cerebrospinal fluid barrier permeability alterations and 2) elucidate the in vivo concentration relationship between prostaglandin E2 (PGE2) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 microg) induced neuroinflammation. Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid barrier permeability. Meningeal NO and cerebrospinal fluid PGE2 were assayed using conventional methods. (Results are expressed as mean +/- S.E.M. of 5-9 rats/group.) Nimesulide failed to prevent blood-cerebrospinal fluid barrier disruption [cerebrospinal fluid Evans blue (micrograms per milliliter): control, 0.22 +/- 0.22*; LPS, 11.58 +/- 0.66; LPS + nimesulide, 10.58 +/- 0.86; *p < 0.05; ANOVA]. Although nimesulide decreased PGE2 (picograms per microliter; p < 0.01) in LPS + nimesulide rats (13.9 +/- 1.96) versus LPS + vehicle (73.8 +/- 12.4), meningeal NO production (picomoles/30 min/10(6) cells; p < 0.01) increased unexpectedly in LPS + nimesulide rats (439 +/- 47) versus LPS + vehicle rats (211 +/- 31). In contrast, aminoguanidine inhibited meningeal NO (picomoles/30 min/10(6) cells; p < 0.005) in LPS + aminoguanidine (111 +/- 20) versus LPS (337 +/- 48) but had no effects (p > 0.05) on PGE2. The in vivo relationship between PGE2 and NO was mathematically described by a biphasic, bell-shaped curve (r2 = 0.42; n = 27 rats; p < 0.0001). Based on these results, inhibition of prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid barrier disruption during neuroinflammation and but also promotes increased meningeal NO production. The in vivo concentration relationship between PGE2 and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.

The influence of lidocaine on the permeability of the blood-cerebrospinal fluid barrier in experimental acute hypercapnia in the rabbit

In a previous study we have provided evidence, that acute experimental hypercapnia due to hypoventilation in the rabbit alters blood-cerebrospinal fluid barrier function in the brain (Pakulski et al. 1998). The purpose of this study therefore was to determine if lidocaine would prevent the observed alterations in the blood-cerebrospinal fluid barrier function. The experiments were conducted in 16 adult Chinchilla rabbits submitted to acute hypercapnia due to mechanical hypoventilation (PaCO2 between 8 - 9.5 kPa over 180 minutes) under pentobarbital anaesthesia. The studied group (n = 8) was treated by lidocaine infusion 10 mg kg-1h-1. After 180 minutes of hypercapnia the value of cerebrospinal fluid-blood index of gentamycin concentration, indicating the permeability of the blood-cerebrospinal fluid barrier, was significantly lower in animals treated with lidocaine (4.03+/-2.32 vs. 19.05+/-5.49; P&lt; 0.01). We conclude that lidocaine may attenuate the increase of blood-cerebrospinal fluid barrier permeability under conditions of experimental acute hypercapnia lasting 180 minutes in the mechanically ventilated rabbit.

Blood-brain exchange routes and distribution of 65Zn in rat brain.

Zinc is essential for normal development and function of the CNS although much is to be learned about brain Zn homeostasis. In these experiments adult male Wistar rats within the weight range 500-600 g were used. Ventriculo-cisternal perfusion was performed to allow the measurement of 65Zn fluxes between blood and csf across the choroid plexuses. Blood-brain or blood-cerebrospinal fluid barrier permeability to 65Zn has been determined by graphical analysis in experiments that lasted between 5 and 180 minutes. Cerebral capillary permeability to 65Zn was found to be low with a K(in) of about 5 x 10(-4)ml/min/g. Choroid plexus permeability to 65Zn was about 12 fold greater, although Zn influx to brain via this route was less than 5% that across cerebral capillaries. The autoradiographic distribution of 65Zn in brain showed regional variation with lowest levels in white matter and high levels in the dentate gyrus and hippocampus.

Blood-cerebrospinal fluid barrier permeability to serum IgG subfractions and measurement of intrathecal IgG synthesis

CSF/serum gradients of IgG subfractions separated by isoelectric focusing (IF) have been measured by high resolving laser densitometry. In patients with normal blood-CSF barrier permeability (N.25) and with barrier damage due to acute idiopathic polyneuropathy (N.15) and to medullary compression (N.17), the CSF/serum gradients of IgG subfractions were negatively correlated with their pI. This electrostatic selectivity appeared to be reverted in barrier damage due to acute meningoencephalitis (N.15). In a series of multiple sclerosis patients (N.31), the CSF/serum gradients of IgG subfractions lacking CSF oligoclonal bands have been used to assess the overall barrier permeability to serum IgG. All intra-BCB synthesized IgG subfractions could be measured by densitometry, whereas with other quantitative formulae, 23–26% of the results were false negatives; the total intrathecal IgG amount ranged from 0.01 to 11 mg/dl. The most frequent and prominent fractions appeared to be cathodic. Electrostatic and steric barrier selectivity must be taken into account when the amount of intrathecal IgG synthesis has to be measured.

Heterogeneous models for blood-cerebrospinal fluid barrier permeability to serum proteins in normal and abnormal cerebrospinal fluid/serum protein concentration gradients

Cerebrospinal fluid (CSF)/serum concentration gradients (Q) of individual proteins (albumin, IgG, α 2-macroglobulin) have been studied in controls and in patients in whom the lumbar CSF flow is altered (medullary compression) or the blood-CSF barrier (BCB) function impaired (acute idiopathic polyneuropathy and acute meningoencephalitis). The analysis of relationships among protein Q has been performed by total and multiple regressions and the actual BCB permeability to individual proteins has been interpreted according to the accepted theoretical porous or vesicular BCB models. The exponential Q-IgG vs. Q-albumin total regression, and the poor Q- α 2-macroglobulin vs. Q-albumin regression found in controls, together with the different multiple regressions among proteins and the high Q-IgG vs. Q-albumin partial regression coefficients found in medullary compression, acute idiopathic polyneuropathy and acute meningoencephalitis, indicated that different permeability mechanisms can be postulated. Heterogeneous, fairly independent permeability BCB mechanisms maintain the normal CSFZ/serum protein concentration gradient. Pinocytotic vesicles or pores of radius exceeding 1000–1500 Å, probably located at the capillary endothelium, account for the main serum-derived CSF protein fraction(s) with large hydrodynamic radius (R). A more selective endothelial vesicular transport with a radius of 250 Å transfers a negligible amount of protein from serum into CSF. Proteins with small R also enter the CSF through a set of selective pores of radius 120 Å, probably at the level of the choroidal epithelium. Pinocytotic vesicles with a radius of 250 Å and increased rate of formation induce the accumulation of proteins below an obstruction of lumbar CSF flow. An increased formation rate of vesicles with a radius of 450 Å can explain the increased capillary permeability in nerve roots in acute idiopathic polyneuropathy. Loss of selectivity was the main feature of BCB in acute meningoencephalitis, and it seemed to be due to pores or vesicles with a radius larger than 1000–1500 Å. The heterogeneity of BCB mechanisms must be taken into account when the intrathecal synthesis of a protein, also derived from serum (for example IgG), has to be measured.

Transport of large molecules from plasma to interstitial fluid and lymph in dogs.

Transport of large molecules from plasma to interstitial fluid and lymph in dogs.

Nature of the Blood-Cerebrospinal Fluid Barrier Permeability Revealed by Isohemagglutinin Tests

Nature of the Blood-Cerebrospinal Fluid Barrier Permeability Revealed by Isohemagglutinin Tests