Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia
| Autor: | Tricoire, Hervé, Palandri, Amandine, Martin, Elodie, Russi, Maria, Rera, Michael, Tricoire, Hérvé, Monnier, Véronique |
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| Přispěvatelé: | Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Études Linguistiques - Corpus, Discours et Sociétés (CEL), Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Rera, Michael, Centre d'Etudes Linguistiques (CEL) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Ataxia Cardiomyopathy [SDV]Life Sciences [q-bio] Neuroscience (miscellaneous) Friedreich’s ataxia lcsh:Medicine Medicine (miscellaneous) Microtubule Cardiotonic Agents Pharmacology Sarcomere General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Immunology and Microbiology (miscellaneous) In vivo lcsh:Pathology medicine Myocyte ComputingMilieux_MISCELLANEOUS Pharmacological screening biology business.industry lcsh:R medicine.disease biology.organism_classification 3. Good health [SDV] Life Sciences [q-bio] Methylene Blue 030104 developmental biology Frataxin biology.protein Drosophila medicine.symptom Drosophila melanogaster business 030217 neurology & neurosurgery lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Cambridge Company of Biologists, 2018, 11 (7), pp.dmm033811. ⟨10.1242/dmm.033811⟩ Disease Models & Mechanisms, Vol 11, Iss 7 (2018) Disease Models & Mechanisms, 2018, 11 (7), pp.dmm033811. ⟨10.1242/dmm.033811⟩ |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.033811 |
| Popis: | Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen in vivo the Prestwick Chemical library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was Paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases. |
| Databáze: | OpenAIRE |
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