Choroid plexus epithelial monolayers – a cell culture model from porcine brain

Baehr, Carsten H.; Reichel, Valeska; Fricker, Gert

doi:10.1186/1743-8454-3-13

Cited by 53 publications

(30 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The basolateral localization of MRP1 at the CPs was confirmed by several other groups of investigators [50,51]. The localization of MRP1 suggests that MRP1 is an efflux of transport of drugs out of the CP.…”

Section: Bcsfbsupporting

confidence: 55%

See 1 more Smart Citation

CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective

Lin

2008

CDM

167

136

View full text Add to dashboard Cite

For drugs that directly act on targets in the central nervous system (CNS), sufficient drug delivery into the brain is a prerequisite for drug action. Systemically administered drugs can reach CNS by passage across the endothelium of capillary vasculatures, the so-called blood-brain barrier (BBB). Literature data suggest that most marketed CNS drugs have good membrane permeability and relatively high plasma unbound fraction, but are not good P-glycoprotein (P-gp) substrates. Therefore, it is important to use the in vitro parameters of P-gp function activity, membrane permeability and plasma unbound fraction as key criteria for lead optimization during the early stage of drug discovery. Evidence from preclinical and clinical studies suggests that drug concentration in cerebrospinal fluid (CSF) appears to be reasonably accurate in predicting unbound drug concentration in the brain. Therefore, CSF can be used as a useful surrogate for in vivo assessment of CNS exposure and provides an important basis for the selection of drug candidates for entry into development. However, it is important to point out that CSF drug concentration is not always an accurate surrogate for predicting unbound drug concentration in the brain. Depending on the physicochemical properties of drugs and the site/timing of CSF sampling, the unbound drug concentration at the biophase within the brain could differ significantly from the corresponding CSF drug concentration.

show abstract

Section: Bcsfbsupporting

confidence: 55%

“…Similarly, mdr1a P-gp was not detected in mice by using high resolution confocal laser scanning microscopy [50]. Recently, it was demonstrated that P-gp was expressed intracellularly in primary porcine CP model [51]. The intracellular localization of P-gp raises the question about the functional role of the protein in the CP.…”

Section: Bcsfbmentioning

confidence: 97%

CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective

Lin

2008

CDM

167

136

View full text Add to dashboard Cite

show abstract

“…Many studies on CSF formation are carried out on cultured epithelial cells in vitro (Angelow et al, 2004; Hosoya et al, 2004; Baehr et al, 2006). As many as 8 methods have been described for measuring CSF formation in vivo (Oreskovic and Klarica, 2010).…”

Section: Discussionmentioning

confidence: 99%

A novel method to study cerebrospinal fluid dynamics in rats

Karimy

Kahle

Kurland

et al. 2015

Journal of Neuroscience Methods

View full text Add to dashboard Cite

Background Cerebrospinal fluid (CSF) flow dynamics play critical roles in both the immature and adult brain, with implications for neurodevelopment and disease processes such as hydrocephalus and neurodegeneration. Remarkably, the only reported method to date for measuring CSF formation in laboratory rats is the indirect tracer dilution method (a.k.a., ventriculocisternal perfusion), which has limitations. New Method Anesthetized rats were mounted in a stereotaxic apparatus, both lateral ventricles were cannulated, and the Sylvian aqueduct was occluded. Fluid exited one ventricle at a rate equal to the rate of CSF formation plus the rate of infusion (if any) into the contralateral ventricle. Pharmacological agents infused at a constant known rate into the contralateral ventricle were tested for their effect on CSF formation in real-time. Results The measured rate of CSF formation was increased by blockade of the Sylvian aqueduct but was not changed by increasing the outflow pressure (0–3 cm of H2O). In male Wistar rats, CSF formation was age-dependent: 0.39±0.06, 0.74±0.05, 1.02±0.04 and 1.40±0.06 µL/min at 8, 9, 10 and 12 weeks, respectively. CSF formation was reduced 57% by intraventricular infusion of the carbonic anhydrase inhibitor, acetazolamide. Comparison with existing methods Tracer dilution methods do not permit ongoing real-time determination of the rate of CSF formation, are not readily amenable to pharmacological manipulations, and require critical assumptions. Direct measurement of CSF formation overcomes these limitations. Conclusions Direct measurement of CSF formation in rats is feasible. Our method should prove useful for studying CSF dynamics in normal physiology and disease models.

show abstract

“…Several in vitro models of the CP have been developed to study the BCSFB function [209], including mouse [210], rat [211], porcine [212,213] and Rhesus macaque [214] primary epithelial cells and immortalized mouse and rat cells [209,211,215,216]. These models can be used to study drug delivery and clearance, as well as transporter function; for instance, the porcine model of CP epithelial cells developed by Baeh et al [213] formed a monolayer with key characteristics of the BCSFB; such as the expression of Mrp1 in the basolateral (blood-facing) membrane, similarly to its location in tissue.…”

Section: In Vitro Models Of the Bcsfb And Babmentioning

confidence: 99%

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

et al. 2019

View full text Add to dashboard Cite

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

show abstract

Choroid plexus epithelial monolayers – a cell culture model from porcine brain

Abstract: Background: The goal of the present study was to develop an in vitro choroid plexus (CP) epithelial cell culture model for studying transport of protein-mediated drug secretion from blood to cerebrospinal fluid (CSF) and vice versa.

Cited by 53 publications

References 45 publications

CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective

CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective

A novel method to study cerebrospinal fluid dynamics in rats

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Contact Info

Product

Resources

About