In Vitro Models of the Blood-Brain Barrier

Neuhaus, Winfried

doi:10.1007/164_2020_370

Cited by 82 publications

(18 citation statements)

References 175 publications

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“…In recent years, substantial progress has been made in the development of direct in vivo measurements of the blood-to-brain transport (e.g., microdialysis [ 3 ] and cerebral open-flow microperfusion [ 4 ]), as well as non-mammalian whole-organism models suitable for the high-throughput screening [ 5 ]. Increasingly relevant and accurate in vitro models are also being developed [ 6 , 7 , 8 ], including cell-free methods such as the widely used parallel artificial membrane permeability assay (PAMPA) or immobilized artificial membrane (IAM) chromatography, brain slices, isolated capillaries, and various cell culture models. Nevertheless, all these approaches obviously require significant amounts of a physical substance, while achieving physiological relevance in a model may be challenging.…”

Section: Introductionmentioning

confidence: 99%

Towards Deep Neural Network Models for the Prediction of the Blood–Brain Barrier Permeability for Diverse Organic Compounds

2020

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Permeation through the blood–brain barrier (BBB) is among the most important processes controlling the pharmacokinetic properties of drugs and other bioactive compounds. Using the fragmental (substructural) descriptors representing the occurrence number of various substructures, as well as the artificial neural network approach and the double cross-validation procedure, we have developed a predictive in silico LogBB model based on an extensive and verified dataset (529 compounds), which is applicable to diverse drugs and drug-like compounds. The model has good predictivity parameters (Q2=0.815, RMSEcv=0.318) that are similar to or better than those of the most reliable models available in the literature. Larger datasets, and perhaps more sophisticated network architectures, are required to realize the full potential of deep neural networks. The analysis of fragment contributions reveals patterns of influence consistent with the known concepts of structural characteristics that affect the BBB permeability of organic compounds. The external validation of the model confirms good agreement between the predicted and experimental LogBB values for most of the compounds. The model enables the evaluation and optimization of the BBB permeability of potential neuroactive agents and other drug compounds.

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Section: Introductionmentioning

confidence: 99%

Towards Deep Neural Network Models for the Prediction of the Blood–Brain Barrier Permeability for Diverse Organic Compounds

2020

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“…relevant models requires considering the improvement of the BBB in vitro model settings and the knowledge arising, thanks Copyright © 2021 JoVE Creative Commons Attribution 3.0 License jove.com November 2021 • 177 • e63134 • Page 12 of 15to animal models. Hence, it needs to consider the complexity of the BBB architecture and the importance of the cell-cell communications to study the BBB under physiological and pathological conditions30 .The protocol presented here describes a method to set up a full human BBB in vitro model comprising the three main cell types of the BBB, without limitation of access to brain tissue.As a multiple cell system, the induction and the maintenance of BBB properties, without the artificial use of tightening compounds, but instead induced by cell-cell communications is more physiologically relevant and in line with the in vivo induction of the BBB properties31 . Hence, the respect of the chronology of the protocol is prime of importance for the success of the protocol.…”

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confidence: 99%

A Triple Culture Cell System Modeling the Human Blood-Brain Barrier

Rizzi

Deligne

Dehouck

et al. 2021

JoVE

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The delivery of drugs to the brain remains a challenge due to the blood-brain barrier's (BBB) highly specific and restrictive properties, which controls and restrict access to the brain parenchyma. However, with the development of nanotechnologies, large panels of new nanomaterials were developed to improve drug delivery, highlighting the need for reliable in vitro microsystems to predict brain penetration in the frame of preclinical assays. Here is a straightforward method to set up a microphysiological system to model the BBB using solely human cells. In its configuration, the model consists of a triple culture including brain-like endothelial cells (BLECs), pericytes, and astrocytes, the three main BBB cellular actors necessary to induce and regulate the BBB properties in a more physiological manner without the requirement of tightening compounds. The model developed in a 12-well plate format, ready after 6 days of triple culture, is characterized in physical properties, gene, and protein expressions and used for polymeric nanogel transport measurement. The model can be used for an extensive range of experiments in healthy and pathological conditions and represents a valuable tool for preclinical assessments of molecule and particle transport, as well as inter-and intracellular trafficking.

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“…In this paper, we examined the BBB crossing capability of T1AM and its endogenous metabolite TA1 by using murine brain endothelial cells (bEnd.3), seeded on transwell inserts as an in vitro BBB model system [ 44 , 45 , 46 ]. Initially, we tested our BBB in vitro model to ascertaining its permeability and bioelectric properties.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

et al. 2021

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Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

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In Vitro Models of the Blood-Brain Barrier

Cited by 82 publications

References 175 publications

Towards Deep Neural Network Models for the Prediction of the Blood–Brain Barrier Permeability for Diverse Organic Compounds

Towards Deep Neural Network Models for the Prediction of the Blood–Brain Barrier Permeability for Diverse Organic Compounds

A Triple Culture Cell System Modeling the Human Blood-Brain Barrier

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

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