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E C de Lange

Publications and source records attributed to E C de Lange.

15 recordsLinked to original sources
PubMed2001

Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging.

SUMMARY: The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57Bl/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57Bl/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

Aging↗
PubMed2001

Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain.

In the present study, we investigated the role of the multidrug resistance (mdr) P-glycoprotein (Pgp) at the blood-brain barrier in the control of access of cortisol and corticosterone to the mouse and human brain. [(3)H]Cortisol poorly penetrated the brain of adrenalectomized wild-type mice, but the uptake was 3.5-fold enhanced after disruption of Pgp expression in mdr 1a(-/-) mice. In sharp contrast, treatment with [(3)H]corticosterone revealed high labeling of brain tissue without difference between both genotypes. Interestingly, human MDR1 Pgp also differentially transported cortisol and corticosterone. LLC-PK1 monolayers stably transfected with MDR1 complementary DNA showed polar transport of [(3)H]cortisol that could be blocked by a specific Pgp blocker, whereas [(3)H]corticosterone transport did not differ between transfected and host cells. Determination of the concentration of both steroids in extracts of human postmortem brain tissue using liquid chromatography mass spectrometry revealed that the ratio of corticosterone over cortisol in the brain was significantly increased relative to plasma. In conclusion, the data demonstrate that in both mouse and human brain the penetration of cortisol is less than that of corticosterone. This finding suggests a more prominent role for corticosterone in control of human brain function than hitherto recognized.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Methodological issues in microdialysis sampling for pharmacokinetic studies.

Microdialysis is an in vivo technique that permits monitoring of local concentrations of drugs and metabolites at specific sites in the body. Microdialysis has several characteristics, which makes it an attractive tool for pharmacokinetic research. About a decade ago the microdialysis technique entered the field of pharmacokinetic research, in the brain, and later also in peripheral tissues and blood. Within this period much has been learned on the proper use of this technique. Today, it has outgrown its child diseases and its potentials and limitations have become more or less well defined. As microdialysis is a delicate technique for which experimental factors appear to be critical with respect to the validity of the experimental outcomes, several factors should be considered. These include the probe; the perfusion solution; post-surgery interval in relation to surgical trauma, tissue integrity and repeated experiments; the analysis of microdialysate samples; and the quantification of microdialysate data. Provided that experimental conditions are optimized to give valid and quantitative results, microdialysis can provide numerous data points from a relatively small number of individual animals to determine detailed pharmacokinetic information. An example of one of the added values of this technique compared with other in vivo pharmacokinetic techniques, is that microdialysis reflects free concentrations in tissues and plasma. This gives the opportunity to assess information on drug transport equilibration across membranes such as the blood-brain barrier, which already has provided new insights. With the progress of analytical methodology, especially with respect to low volume/low concentration measurements and simultaneous measurement of multiple compounds, the applications and importance of the microdialysis technique in pharmacokinetic research will continue to increase.

Animals↗
PubMed2000

In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin.

The role of mdr1a-encoded P-glycoprotein on transport of several fluoroquinolones across the blood-brain barrier was investigated. In vitro, P-glycoprotein substrates were selected by using a confluent monolayer of MDR1-LLC-PK1 cells. The inhibition of fluoroquinolones (100 microM) on transport of rhodamine-123 (1 microM) was compared with P-glycoprotein inhibitors verapamil (20 microM) and SDZ PSC 833 (2 microM). Subsequently, transport polarity of fluoroquinolones was studied. Sparfloxacin showed the strongest inhibition (26%) and a large polarity in transport, by P-glycoprotein activity. In vivo, using mdr1a (-/-) and wild-type mice, brain distribution of pefloxacin, norfloxacin, ciprofloxacin, fleroxacin and sparfloxacin was determined at 2, 4, and 6 h following intra-arterial infusion (50 nmol/min). Brain distribution of sparfloxacin was clearly higher in mdr1a (-/-) mice compared with wild-type mice. Sparfloxacin was infused (50 nmol/min) for 1, 2, 3 and 4 h in which intracerebral microdialysis was performed. At 4 h, in vivo recovery (dynamic-no-net-flux method) was 6.5+/-2.2 and 1.5+/-0.5%; brain(ECF) concentrations were 5.1+/-0.2 and 26+/-21 microM; and total brain concentrations were 7.2+/-0.3 and 23+/-0.3 microM in wild-type and mdr1a (-/-) mice, respectively. Plasma concentrations were similar (18.4+/-0.7 and 17.9+/-0.5 microM, respectively). In conclusion, sparfloxacin enters the brain poorly mainly because of P-glycoprotein activity at the blood-brain barrier.

4-Quinolones↗
PubMed1999

The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice.

1. The aim of this study was to investigate whether blood-brain barrier transport of morphine was affected by the absence of mdr1a-encoded P-glycoprotein (Pgp), by comparing mdr1a (-/-) mice with mdr1a (+/+) mice. 2. Mdr1a (-/-) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic-no-net-flux method. 3. Retrodialysis loss of morphine and nalorphine was similar in vivo. Unbound brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with corresponding total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic-no-net-flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (-/-) and (+/+) mice, respectively. 4. No significant differences in the pharmacokinetics of the metabolite morphine-3-glucoronide were observed between (-/-) and (+/+) mice. 5. In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123.

PURPOSE: The effect of P-glycoprotein (Pgp) on brain distribution using mdr1a (-/-) mice was investigated. METHODS: Fluorescein (Flu) and FD-4 were used to check whether blood-brain barrier (BBB) integrity was maintained in mdr1a (-/-) mice. The Pgp substrate rhodamine-123 (R123) was infused and total brain, blood and brain microdialysate concentrations in mdr1a (-/-) mice and wild-type mice were compared. RESULTS: Maintenance of BBB integrity was indicated by equal total brain/blood ratios of Flu and FD-4 in both mice types. R123 concentrations in brain after i.v. infusion were about 4-fold higher in mdr1a (-/-) than in wild-type mice (P < 0.05), without changes in blood levels. After microdialysis experiments the same results were found, excluding artifacts in the interpretation of Pgp functionality by the use of this technique. However the 4-fold ratio in brain was not reflected in corresponding microdialysates. No local differences of R123 in the brain were found. By the no-net-flux method in vivo recovery appeared to 4.6-fold lower in mdrla (-/-) mice compared with wild-type mice. CONCLUSIONS: Pgp plays an important role in R123 distribution into the brain. Using intracerebral microdialysis, changes in in vivo recovery by the absence or inhibition of Pgp (or active efflux in general) need to be considered carefully.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice.

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of [3H]-dexamethasone in the brain. [3H]-dexamethasone (4 microg/kg mouse) was administered s.c. to adrenalectomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of [3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concentration in pituitary was not affected by mdr1a gene disruption. The GR messenger RNA expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the present study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-brain barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexamethasone poorly substitutes for depletion of the endogenous glucocorticoid from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier.

For the study of the pharmacokinetics of drugs in the brain a number of in vivo techniques is available, including autoradiography, imaging techniques, cerebrospinal fluid sampling and in vivo voltammetry, which all have their specific advantages and limitations. Intracerebral microdialysis is a relatively new in vivo technique. It permits monitoring of local concentrations of drugs and metabolites at specific sites in the brain which makes it an attractive tool for pharmacokinetic research. In the use of this technique a number of factors should be considered. These include: type of probe, surgical trauma, post-surgery interval, perfusion flow rate, as well as composition and temperature of the perfusion medium. In particular in studies on drug transport across the blood-brain barrier (BBB), effects of insertion of the probe on BBB functionality is important. It appears that BBB functionality is not significantly affected if surgical and experimental conditions are well-controlled. The relationship between dialysate concentrations and those in the extracellular fluid of the periprobe tissue, the recovery of the drug, depends on periprobe processes governing the actual concentration of the drug at that site. These include extracellular-microvascular exchange, metabolism, and diffusion of the drug. Several methods have been proposed to determine recovery values. In particular the no net flux method and the extended no net flux method are useful in practice. Several microdialysis studies on BBB transport of drugs are presented showing that intracerebral microdialysis is capable to assess local BBB transport profiles. Compared with other in vivo techniques, intracerebral microdialysis is the only (affordable) technique that offers the possibility to monitor local BBB transport of drugs in unanaesthetized animals, under physiological and pathological conditions.

Animals↗
PubMed1997

Drug equilibration across the blood-brain barrier--pharmacokinetic considerations based on the microdialysis method.

PURPOSE: The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. METHODS: Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. RESULTS: Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. CONCLUSIONS: Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.

Biological Transport, Active↗
PubMed1995

Repeated microdialysis perfusions: periprobe tissue reactions and BBB permeability.

In the present paper the time course of brain tissue changes as evoked by a microdialysis probe and repeated dialysis procedures was examined by semiquantitative histology. The reactions to the presence of the probe as such were minimal. However, after more than two repeated perfusion procedures, tissue scores of hypercellularity and infiltration of granulocytes increased. It is concluded that the frequent use of repeated dialysis procedures may give rise to tissue effects parallelled by changes in BBB permeability. This has to be taken into account when intracerebral microdialysis is applied repeatedly within the same animal.

Animals↗
PubMed1995

The use of intracerebral microdialysis to determine changes in blood-brain barrier transport characteristics.

The aim of this study was to determine whether changes in the transport of drugs into the brain could be determined by in vivo intracerebral microdialysis. Atenolol was used as a model drug to determine blood-brain barrier (BBB) transport characteristics. In rats, unilateral opening of the blood-brain barrier was achieved by infusion of hyperosmolar mannitol (25%, w/v) into the left internal carotid artery. BBB transport, expressed as the ratio of the area under the curve (AUC) of atenolol in brain extracellular fluid over plasma, was three times higher for the mannitol treated hemisphere as compared with the contralateral brain or after infusion of saline, being (mean +/- SEM) 0.094 +/- 0.024 (n = 16), 0.029 +/- 0.007 (n = 12) and 0.030 +/- 0.009 (n = 12) respectively. Further evaluation of the data indicated that for experiments performed in the morning the mannitol infusion had little effect on the extent of transport of atenolol into the brain, while in the afternoon BBB transport was about 10-fold higher than in the contralateral and saline group. The mean "afternoon" ratios +/- SEM were 0.155 +/- 0.038 (n = 8), 0.012 +/- 0.003 (n = 6) and 0.018 +/- 0.006 (n = 6) respectively. It is concluded that intracerebral microdialysis is capable of revealing changes in BBB transport and regional and time-dependent differences in drug levels can be demonstrated with the use of this technique.

Animals↗
PubMed1995

The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain.

PURPOSE: The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated. METHODS: Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX. RESULTS: MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250%). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65%). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain. CONCLUSIONS: Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Animals↗
PubMed1995

Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated.

Acetaminophen↗
PubMed1994

Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain.

The purpose of this investigation was to determine the effect of experimental conditions on the concentrations of atenolol and acetaminophen in brain microdialysate, and to investigate the feasibility of performing repeated experiments within individual rats. Following intravenous bolus administration, reproducible concentration-time profiles were obtained in plasma and in brain dialysate. Based on corrections for in vitro recoveries of the intracerebral probe, the estimated ratio of the AUC in brain extracellular fluid (AUCbrain ECF) over the AUC in plasma (AUCplasma) +/- S.E.M. was 3.8 +/- 0.6% (n = 6) for atenolol and 18 +/- 2% (n = 6) for acetaminophen. Upon intracerebroventricular administration, interanimal differences in kinetics of acetaminophen in brain dialysate were observed while the concentrations of atenolol were below the detection limit of the assay. The influence of the use of isotonic versus hypotonic perfusate solutions on AUCbrain ECF values after intravenous bolus administration of both drugs was determined. Repeated experiments with the isotonic perfusate (24, 48 and 78 h post-surgery) resulted in AUCbrain ECF values with the ratio of 100: 98: 76% for acetaminophen and 100: 103: 98% for atenolol. Using a hypotonic perfusion solution the ratio of AUCbrain ECF values was 100: 154: 114% for acetaminophen and 100: 378: 427% for atenolol. A clear effect of the temperature of the hypotonic perfusate (24 vs 38 degrees C) on acetaminophen AUCbrain ECF values was revealed. The ratio of AUCbrain ECF values obtained at 24: 38 degrees C was 192: 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗