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Title: | Effect of diazoxide on Friedreich ataxia models |
Authors: | Santoro, A Virmouni, SA Paradies, E Coa, VLV Al-Mahdawi, S Khoo, M Porcelli, V Vozza, A Perrone, M Denora, N Taroni, F Merla, G Palmieri, L Pook, MA Marobbio, CMT |
Keywords: | Friedreich ataxia;cell lines;mitochondrial proteins;cerebellum;mice;diazoxide;mtor serine-threonine kinases |
Issue Date: | 8-Jan-2018 |
Publisher: | Oxford University Press |
Citation: | Santoro, A., Anjomani Virmouni, S., Paradies, E., Coa, V.L.V., Al-Mahdawi, S., Khoo,M., Porcelli, V., Vozza, A., Perrone, M., Denora, N., Taroni, F., Merla, G., Palmieri, L., Pook, M. and Marobbio, C.M.T. (2018) 'Effect of diazoxide on Friedreich ataxia models', Human Molecular Genetics, 27 (6), pp. 992–1001. doi: 10.1093/hmg/ddy016. |
Abstract: | Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3 mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity, and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials. |
URI: | https://bura.brunel.ac.uk/handle/2438/16912 |
DOI: | https://doi.org/10.1093/hmg/ddy016 |
ISSN: | 0964-6906 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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Fulltext.pdf | This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio, Effect of diazoxide on Friedreich ataxia models, Human Molecular Genetics, Volume 27, Issue 6, 15 March 2018, Pages 992–1001, is available online at:https://academic.oup.com/hmg/article/27/6/992/4793004 | 2.09 MB | Adobe PDF | View/Open |
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