Application of an in Vitro Blood–Brain Barrier Model in the Selection of Experimental Drug Candidates for the Treatment of Huntington’s Disease
| Autor: | Mark Rose, Odalys Gonzalez Paz, Giulio Auciello, Annalise Di Marco, Todd Herbst, Ignacio Muñoz-Sanjuán, Domenico Vignone, Edith Monteagudo, Vinod Khetarpal, Matteo Zini, Maria Rosaria Battista, Laura Orsatti, Vincenzo Summa, Celia Dominguez, Leticia M Toledo-Sherman, Ivan Fini, Antonella Cellucci |
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| Přispěvatelé: | Di Marco, A., Gonzalez Paz, O., Fini, I., Vignone, D., Cellucci, A., Battista, M. R., Auciello, G., Orsatti, L., Zini, M., Monteagudo, E., Khetarpal, V., Rose, M., Dominguez, C., Herbst, T., Toledo-Sherman, L., Summa, V., Munoz-Sanjuan, I. |
| Rok vydání: | 2019 |
| Předmět: |
Swine
Pharmaceutical Science 02 engineering and technology Pharmacology efflux transporter 030226 pharmacology & pharmacy brain penetration Rats Sprague-Dawley 0302 clinical medicine Drug Discovery Electric Impedance Coculture Technique Cells Cultured Cerebral Cortex Endothelial Cell Tight junction Tight Junction Drug discovery Chemistry Huntington's disease Biological activity 021001 nanoscience & nanotechnology Huntington Disease medicine.anatomical_structure Blood-Brain Barrier Molecular Medicine Central Nervous System Agent CNS Astrocyte 0210 nano-technology ATP-Binding Cassette Transporter Central nervous system Blood–brain barrier Models Biological Permeability Tight Junctions Capillary Permeability 03 medical and health sciences In vivo Huntingtin Protein medicine Animals Solute Carrier Protein Solute Carrier Proteins Animal Endothelial Cells medicine.disease Coculture Techniques Rats Astrocytes transport Rat ATP-Binding Cassette Transporters Central Nervous System Agents |
| Zdroj: | Molecular Pharmaceutics. 16:2069-2082 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | 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. © |
| Databáze: | OpenAIRE |
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