Application of an in Vitro Blood-Brain Barrier Model in the Selection of Experimental Drug Candidates for the Treatment of Huntington's Disease

Mol Pharm. 2019 May 6;16(5):2069-2082. doi: 10.1021/acs.molpharmaceut.9b00042. Epub 2019 Apr 4.


Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the huntingtin protein. For drug candidates targeting HD, the ability to cross the blood-brain barrier (BBB) and reach the site of action in the central nervous system (CNS) is crucial for achieving pharmacological activity. To assess the permeability of selected compounds across the BBB, we utilized a two-dimensional model composed of primary porcine brain endothelial cells and rat astrocytes. Our objective was to use this in vitro model to rank and prioritize compounds for in vivo pharmacokinetic and brain penetration studies. The model was first characterized using a set of validation markers chosen based on their functional importance at the BBB. It was shown to fulfill the major BBB characteristics, including functional tight junctions, high transendothelial electrical resistance, expression, and activity of influx and efflux transporters. The in vitro permeability of 54 structurally diverse known compounds was determined and shown to have a good correlation with the in situ brain perfusion data in rodents. We used this model to investigate the BBB permeability of a series of new HD compounds from different chemical classes, and we found a good correlation with in vivo brain permeation, demonstrating the usefulness of the in vitro model for optimizing CNS drug properties and for guiding the selection of lead compounds in a drug discovery setting.

Keywords: CNS; Huntington’s disease; blood−brain barrier; brain penetration; efflux transporters; permeability; transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Astrocytes / metabolism
  • Blood-Brain Barrier / metabolism*
  • Capillary Permeability / physiology
  • Cells, Cultured
  • Central Nervous System Agents / therapeutic use*
  • Cerebral Cortex / cytology
  • Coculture Techniques
  • Drug Discovery / methods*
  • Electric Impedance
  • Endothelial Cells / metabolism
  • Huntington Disease / drug therapy*
  • Models, Biological*
  • Permeability
  • Rats
  • Rats, Sprague-Dawley
  • Solute Carrier Proteins / metabolism
  • Swine
  • Tight Junctions / metabolism


  • ATP-Binding Cassette Transporters
  • Central Nervous System Agents
  • Solute Carrier Proteins