An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms, Hans Christian Cederberg; Hersom, Maria; Kuhlmann, Louise Borella; Badolo, Lasina; Nielsen, Carsten Uhd; Brodin, Birger

doi:10.1208/s12248-014-9628-1

Cited by 42 publications

(52 citation statements)

References 65 publications

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“…In 1974, the first documented successful culture of bovine cerebral cortex endothelial cells on nylon sieves was published . The most common platform of in vitro models used today is created using Transwells (Corning Inc., Corning, NY) and most publications are reported using 10 μm thick polystyrene or polycarbonate membranes with 400 nm pores with a 10 8 pores/mm 2 pore density …”

Section: In Vitro Modelsmentioning

confidence: 99%

“…46 The most common platform of in vitro models used today is created using Transwells (Corning Inc., Corning, NY) and most publications are reported using 10 :m thick polystyrene or polycarbonate membranes with 400 nm pores with a 10 8 pores/mm 2 pore density. 28,[47][48][49][50][51][52][53][54] The models can be developed using one, two, or more cell types, as described below. The endothelial cells are usually grown in the upper (luminal) compartment of the Transwell in cell-specific growth medium.…”

Section: In Vitro Modelsmentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Blood–Brain Barrier Models—An Overview of Established Models and New Microfluidic Approaches

Wolff

Antfolk

Brodin

et al. 2015

Journal of Pharmaceutical Sciences

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169

142

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Section: In Vitro Modelsmentioning

confidence: 99%

Section: In Vitro Modelsmentioning

confidence: 99%

In Vitro Blood–Brain Barrier Models—An Overview of Established Models and New Microfluidic Approaches

Wolff

Antfolk

Brodin

et al. 2015

Journal of Pharmaceutical Sciences

Self Cite

169

142

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“…In order to evaluate the possible interactions with molecules that could influence OligoGM1 availability to hBLECs and the transport to the receiving side, 0.1% (w/v) bovine serum albumin (BSA) was added to 50 μM plus 1 × 10 6 dpm OligoGM1-RH solutions to mimic the blood serum protein content [35]. No difference in the rate of transport was revealed after 60 min of incubation by the comparative analysis of BSA-OligoGM1 and OligoGM1 solutions-excluding a BSA disturbance on the OligoGM1 passage-in the tested conditions ( Figure 6c), suggesting the possibility of no interference of serum protein in the availability of OligoGM1 in vivo.…”

Section: Influence Of Bsamentioning

confidence: 99%

“…To evaluate the possible influence of plasma serum on OligoGM1 transport, RH buffer + 0.1% BSA (w/v) was used as the working solution for the apical side to mimic the protein content of plasma serum [35]. The experiments were conducted for up to 60 min.…”

Section: Direct Transport (Apical To Basolateral a → B)mentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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“…Cocultures have been widely employed in the recent years for the evaluation of drug permeability. A commonly used approach to better mimic the BBB consists on the coculture of a rat primary culture [183] or cell line of astrocytes [184] with BMVEC from rat [147,149,185], porcine [183,184], bovine [177,178,186] or human cells to obtain an improved barrier phenotype characterized by a higher TEER or even increased functionality of ABC transporters [186], as observed for P-gp in a rat astrocyte-bovine brain endothelial cells system [187]. For instance, the tightness of the monolayer formed by hPSC-derived brain endothelial cells is increased by coculture with rat astrocytes [158].…”

Section: In Vitro Models Of the Bbbmentioning

confidence: 99%

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

et al. 2019

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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.

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An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Cited by 42 publications

References 65 publications

In Vitro Blood–Brain Barrier Models—An Overview of Established Models and New Microfluidic Approaches

In Vitro Blood–Brain Barrier Models—An Overview of Established Models and New Microfluidic Approaches

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

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

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