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Laboratory | Pharmacology | Brain


LEMM

Cellular models development for the study of blood-brain barrier

Published on 27 November 2017
Cellular models development for the study of the blood-brain barrier for pharmacokinetics, neuropharmacology and neurotoxicology.

Team Leader
Aloïse Mabondzo
aloise.mabondzo@cea.fr

 To better predict the entry of drug candidates in the brain, we develop and validate animal (rat, mouse, non-human primate) and human cellular models of blood-brain barrier (BBB). These models combine two primary cell types: microvascular endothelial cells, developed on a semi-permeable membrane, and glial cells. These models present the main features of the BBB in vivo. For example we have demonstrated a correlation between the passage of human BBB in vitro and brain penetration in vivo in humans by using radioligands and Positron Emission Tomography (PET).

The team is involved in the NEURATRIS project, funded by the investments for the future (National Infrastructures in Biology and Health), in the establishment of a platform for pediatric BBB models. In addition to their applications in pharmacokinetics, these models are used in the fields of pharmacology and toxicology, as illustrated by the three below-mentioned projects

​Cellular Model for the evaluation of drug candidates against Alzheimer's disease

One of the obstacles to the discovery of effective drugs for Alzheimer's disease (AD) is the lack of models perfectly mimicking the disease.
Current models which are based on in silico tests or the use of transgenic animals are not very effective for evaluating drug candidates. We are looking to set up approaches combining the use of cellular tools and a pharmacological agent capable of inducing a selective production of Aß-42 peptide (considered one of the most toxic species of Aß peptides), the phosphorylation of the Tau protein and the reduction of the "synaptophysin", involved in the synaptic connections. Using this model allows to assess molecules collections of daily exposure, natural or anthropogenic, capable of acting as exogenous factors that contribute to the development of AD. This project, jointly being conducted by various academic institutions and industrial partners, was initiated with the FUI (Fonds Unique Interministériel).


Physiology of the blood-brain barrier during cerebral development and targeting of drug candidates

To complete its limited and selective permeability, the blood-brain barrier has, in addition to its physical structure, specialized membrane transporters (influx and efflux) that play a key role in the pharmacokinetics and pharmacological activity of many drugs. We aim to understand how the activity of these transporters is regulated during brain development and in the context of neuroinflammation (ANRS Program), to optimize the entry of drugs into the central nervous system. Thus, we are involved in a research program (the Lejeune Foundation) to improve the release in the brain of creatine derivatives for the treatment of a rare brain metabolic disease associated with creatine transporter deficiency. This project is conducted in partnership with another team from the institute (IBITECS/SCBM) and with the INSERM U393 unit of the Necker Hospital, Pr Pascale De Lonlay. Finally, we are involved in a peptide and macromolecule vectorization project funded under a FP7-TRANS-INT European program. This project involves various European academic institutions and industrials (Sanofi-Aventis, Roche Diagnostic...).


Neurotoxicology

The objectives of this research program are:

  • Compare and characterize the brain penetration and neurotoxicity profile of drug  candidates and nanoparticles (NanoTrans, DIMSent Programs)
  • Identify molecular signatures characterizing neurotoxicity mechanisms for these molecules;
  • Ultimately develop integrated models of neurotoxicity.