A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models
Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a...
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Frontiers Media S.A.
2022-05-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.830650/full |
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author | Rosella Abeti Mittal Jasoliya Sahar Al-Mahdawi Mark Pook Cristina Gonzalez-Robles Chun Kiu Hui Gino Cortopassi Paola Giunti |
author_facet | Rosella Abeti Mittal Jasoliya Sahar Al-Mahdawi Mark Pook Cristina Gonzalez-Robles Chun Kiu Hui Gino Cortopassi Paola Giunti |
author_sort | Rosella Abeti |
collection | DOAJ |
description | Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology. |
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spelling | doaj.art-dda4674985d74004abe28af246f534452022-12-22T02:39:41ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-05-01910.3389/fmolb.2022.830650830650A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA ModelsRosella Abeti0Mittal Jasoliya1Sahar Al-Mahdawi2Mark Pook3Cristina Gonzalez-Robles4Chun Kiu Hui5Gino Cortopassi6Paola Giunti7Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United KingdomDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United StatesDepartment of Life Sciences, Institute of Environment, Health, and Societies, College of Health and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, United KingdomDepartment of Life Sciences, Institute of Environment, Health, and Societies, College of Health and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, United KingdomAtaxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United KingdomDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United StatesAtaxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United KingdomFriedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.https://www.frontiersin.org/articles/10.3389/fmolb.2022.830650/fullFriedreich’s Ataxia (FA)Frataxin (FXN)Dimethyl fumarate (DMF)Resveratrol (Resv)Mitochondrial membrane potential (ΔΨm)Reactive Oxygen species (ROS) |
spellingShingle | Rosella Abeti Mittal Jasoliya Sahar Al-Mahdawi Mark Pook Cristina Gonzalez-Robles Chun Kiu Hui Gino Cortopassi Paola Giunti A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models Frontiers in Molecular Biosciences Friedreich’s Ataxia (FA) Frataxin (FXN) Dimethyl fumarate (DMF) Resveratrol (Resv) Mitochondrial membrane potential (ΔΨm) Reactive Oxygen species (ROS) |
title | A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models |
title_full | A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models |
title_fullStr | A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models |
title_full_unstemmed | A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models |
title_short | A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models |
title_sort | drug combination rescues frataxin dependent neural and cardiac pathophysiology in fa models |
topic | Friedreich’s Ataxia (FA) Frataxin (FXN) Dimethyl fumarate (DMF) Resveratrol (Resv) Mitochondrial membrane potential (ΔΨm) Reactive Oxygen species (ROS) |
url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.830650/full |
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