Drug Repurposing for Duchenne Muscular Dystrophy: The Monoamine Oxidase B Inhibitor Safinamide Ameliorates the Pathological Phenotype in mdx Mice and in Myogenic Cultures From DMD Patients

Frontiers in Physiology
Libero VitielloMarcella Canton

Abstract

Oxidative stress and mitochondrial dysfunction play a crucial role in the pathophysiology of muscular dystrophies. We previously reported that the mitochondrial enzyme monoamine oxidase (MAO) is a relevant source of reactive oxygen species (ROS) not only in murine models of muscular dystrophy, in which it directly contributes to contractile impairment, but also in muscle cells from collagen VI-deficient patients. Here, we now assessed the efficacy of a novel MAO-B inhibitor, safinamide, using in vivo and in vitro models of Duchenne muscular dystrophy (DMD). Specifically, we found that administration of safinamide in 3-month-old mdx mice reduced myofiber damage and oxidative stress and improved muscle functionality. In vitro studies with myogenic cultures from mdx mice and DMD patients showed that even cultured dystrophic myoblasts were more susceptible to oxidative stress than matching cells from healthy donors. Indeed, upon exposure to the MAO substrate tyramine or to hydrogen peroxide, DMD muscle cells displayed a rise in ROS levels and a consequent mitochondrial depolarization. Remarkably, both phenotypes normalized when cultures were treated with safinamide. Given that safinamide is already in clinical use for neurological ...Continue Reading

References

Nov 21, 1998·Free Radical Biology & Medicine·L BenovI Fridovich
Jan 8, 1999·Journal of the Neurological Sciences·M H DisatnikT A Rando
Dec 26, 2001·Nature Structural Biology·Claudia BindaAndrea Mattevi
Nov 1, 2002·American Journal of Physical Medicine & Rehabilitation·Thomas A Rando
Apr 23, 2003·Free Radical Biology & Medicine·M Christine Rodriguez, Mark A Tarnopolsky
Nov 20, 2003·Nature Genetics·William A IrwinPaolo Bonaldo
Nov 6, 2004·The Journal of Physiology·Ella W YeungDavid G Allen
Mar 23, 2006·Nature Reviews. Neuroscience·Moussa B H YoudimKeith F Tipton
Sep 14, 2006·Muscle & Nerve·Richard M KeelingAnne M Connolly
Sep 15, 2006·Nature Reviews. Molecular Cell Biology·Kay E Davies, Kristen J Nowak
Nov 11, 2006·Journal of Applied Physiology·James G Tidball, Michelle Wehling-Henricks
Jan 12, 2007·Proceedings of the National Academy of Sciences of the United States of America·Alessia AngelinPaolo Bernardi
Jun 19, 2007·American Journal of Physiology. Heart and Circulatory Physiology·Iwan A Williams, David G Allen
Feb 9, 2008·The Journal of Physiology·Nicholas P WhiteheadDavid G Allen
Mar 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Luciano MerliniPaolo Bernardi
Jun 17, 2009·Biochemical and Biophysical Research Communications·Marta OnopiukKrzysztof Zabłocki
Nov 17, 2009·Journal of Applied Physiology·Bert BlaauwCarlo Reggiani
Nov 23, 2010·Nature Reviews. Immunology·Grace Y Chen, Gabriel Nuñez
Apr 24, 2013·Nature Reviews. Genetics·Rebecca J FaircloughKay E Davies
May 15, 2013·The International Journal of Biochemistry & Cell Biology·Jonghyun ShinAshok Kumar
Mar 13, 2014·Journal of Muscle Research and Cell Motility·Marcella CantonFabio Di Lisa
Aug 8, 2015·Science Translational Medicine·Amy S RosenbergJanet Woodcock
Nov 17, 2015·Nature Medicine·Nicolas A DumontMichael A Rudnicki
Sep 15, 2016·Proceedings of the National Academy of Sciences of the United States of America·Erik P RaderKevin P Campbell
May 10, 2017·Current Opinion in Pharmacology·Simon Guiraud, Kay E Davies

❮ Previous
Next ❯

Citations

Dec 6, 2019·International Journal of Molecular Sciences·Libero VitielloMarcella Canton
May 18, 2021·Frontiers in Pharmacology·Mahyar Ostadkarampour, Edward E Putnins

❮ Previous
Next ❯

Methods Mentioned

BETA
deamination
force measurements
electrophoreses
biopsies

Software Mentioned

Metamorph
ImageJ
Metafluor
Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.