In vitro model for evaluating drug transport across the blood–brain barrier

U325 INSERM, Institut Pasteur, 59019 Lille, France
Advanced drug delivery reviews (Impact Factor: 11.96). 05/1999; 36(2-3):165-178. DOI: 10.1016/S0169-409X(98)00083-0
Source: PubMed

ABSTRACT The passage of substances across the blood–brain barrier (BBB) is regulated in the cerebral capillaries, which possess certain distinct different morphological and enzymatic properties compared with the capillaries of other organs. Investigations of the functional characteristics of brain capillaries have been facilitated by the use of cultured brain endothelial cells, but in most studies some characteristics of the in vivo BBB are lost. To provide an in vitro system for studying brain capillary functions, we have developed a process of coculture that closely mimics the in vivo situation by culturing brain capillary endothelial cells on one side of a filter and astrocytes on the other. In order to assess the drug transport across the blood–brain barrier, we compared the extraction ratios in vivo to the permeability of the in vitro model. The in vivo and the in vitro values showed a strong correlation. The relative ease with which such cocultures can be produced in large quantities facilitates the screening of new centrally active drugs. This model provides an easier, reproducible and mass-production method to study the blood–brain barrier in vitro.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Using a relevant in vitro blood brain barrier (BBB) model developed in our laboratory 20 years ago, we investigated the role of low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) at the BBB, in particular at the brain capillary endothelial cells (BCECs) and pericytes level.•The results indicate that Aβ peptide transport across the BCEC monolayer involves a transcellular route.•However, competition experiments using an inhibitor of this receptor discard the involvement of this cellular receptor in BCECs processes.•In contrast, results show a strong transcriptional expression of LRP1 in pericytes and suggest its implication in Aβ endocytosis.•Moreover, the observations of pericytes contraction and local downregulation of LRP1 in response to Aβ treatment provide interesting perspectives for studying these cells’ involvement in the metabolism of brain Aβ peptides.
    Brain Research 10/2014; 1594. DOI:10.1016/j.brainres.2014.10.047 · 2.83 Impact Factor
  • Source
    Frontiers in Psychiatry 09/2014; 5:128. DOI:10.3389/fpsyt.2014.00128
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The majority of therapeutics, small molecule or biologics, developed for the CNS do not penetrate the blood-brain barrier (BBB) sufficiently to induce pharmacologically meaningful effects on CNS targets. To improve the efficiency of CNS drug discovery, several in vitro models of the BBB have been used to aid early selection of molecules with CNS exposure potential. However, correlative studies suggest relatively poor predictability of in vitro BBB models underscoring the need to combine in vitro and in vivo BBB penetration assessment into an integrated preclinical workflow. Areas covered: This review gives a brief general overview of in vitro and in vivo BBB models used in the pre-clinical evaluation of CNS-targeting drugs, with particular focus on the recent progress in developing humanized models. The authors discuss the advantages, limitations, in vitro-in vivo correlation, and integration of these models into CNS drug discovery and development with the aim of improving translation. Expert opinion: Often, a simplistic rationalization of the CNS drug discovery and development process overlooks or even ignores the need for an early and predictive assessment of the BBB permeability. Indeed, past failures of CNS candidates in clinical trials argue strongly that the early deployment of in vitro and in vivo models for assessing BBB permeability, mechanisms of transport and brain exposure of leads, and the co-development of BBB delivery strategies will improve translation and increase the clinical success of CNS pipelines.
    Expert Opinion on Drug Discovery 11/2014; 10(2):1-15. DOI:10.1517/17460441.2015.974545 · 3.47 Impact Factor

Full-text (2 Sources)

Available from
May 28, 2014