| Autor: |
Mike Dragunow, Emma L. Scotter, Clinton Turner, Peter Heppner, Victor Birger Dieriks, Maurice A. Curtis, Patrick Schweder, Miranda Aalderink, Deidre Jansson, Leon Smyth, Justin Rustenhoven, Rebecca Johnson, Richard L.M. Faull, Sheryl Feng, Edward W. Mee |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.04.15.043588 |
| Popis: |
Neuroinflammation is a key component of virtually all neurodegenerative diseases; preceding neuronal loss and associating directly with cognitive impairment. Neuroinflammatory signals can originate and be amplified at barrier tissues such as brain vasculature, surrounding meninges and the choroid plexus. We designed a high-throughput screening system to target inflammation in cells of the blood-brain barrier (primary human pericytes and endothelia) and microglia enabling us to target human disease-specific inflammatory modifiers. Screening an FDA-approved drug library we identified digoxin and lanatoside C, members of the cardiac glycoside family as inflammatory modulating drugs that work in blood-brain barrier cells. A novelex vivoassay of leptomeningeal and choroid plexus explants further confirmed that these drugs maintain their function in 3D cultures of brain border tissues. While current therapeutic strategies for the treatment of neurodegenerative diseases are missing the mark in terms of targets, efficacy and translatability, our innovative approach usingin vitroandex vivohuman barrier cells and tissues to target neuroinflammatory pathways is a step forward in drug development and testing, and brings us closer to translatable treatments for human neurodegenerative disease.One Sentence SummaryWe have identified cardiac glycosides as powerful regulators of neuroinflammatory pathways in brain-barrier tissues such as vasculature, meninges and choroid plexus. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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