Application of an in Vitro Blood–Brain Barrier Model in the Selection of Experimental Drug Candidates for the Treatment of Huntington’s Disease
| العنوان: | Application of an in Vitro Blood–Brain Barrier Model in the Selection of Experimental Drug Candidates for the Treatment of Huntington’s Disease |
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| المؤلفون: | 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 |
| المساهمون: | 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. |
| المصدر: | Molecular Pharmaceutics. 16:2069-2082 |
| بيانات النشر: | American Chemical Society (ACS), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. © |
| تدمد: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.9b00042 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::27cfdbc702df6685a64c4f15855675c2 https://doi.org/10.1021/acs.molpharmaceut.9b00042 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....27cfdbc702df6685a64c4f15855675c2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15438392 15438384 |
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| DOI: | 10.1021/acs.molpharmaceut.9b00042 |