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

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 disorders, our findings could pave the way toward a promising translation into clinical trials for DMD patients as a classic case of drug repurposing.

Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

“…Consistently, treatment with pargyline, an inhibitor of both MAO-A and MAO-B, reduced tropomyosin oxidation and led to improvement of the dystrophic phenotype in mdx and col6a1 −/− mice [72]. MAO has also been shown to be overactivated in myoblasts from patients with collagen VI myopathies and DMD [55,56]. More recently, novel and better tolerated inhibitors of the B isoform (MAO-Bi) have been introduced in the clinic for neurological disorders [76].…”

“…Oxidative stress and mitochondrial dysfunction are known to play a key role in DMD [55,67,68,69,70,71,72]. A crucial source of reactive oxygen species (ROS) in dystrophic muscles is monoamine oxidase (MAO) [55,56,72], a mitochondrial enzyme widely studied for its role in the central nervous system [57]. The two isoforms of MAO, A and B, are located in the outer mitochondrial membrane and catalyze the oxidative deamination of different biogenic amines to generate aldehydes and H 2 O 2 .…”

“…The two isoforms of MAO, A and B, are located in the outer mitochondrial membrane and catalyze the oxidative deamination of different biogenic amines to generate aldehydes and H 2 O 2 . Pathologic excess of H 2 O 2 have been shown to be involved in the oxidation of contractile proteins both in ischemic heart and dystrophic skeletal muscle [56,72,73,74,75]. Consistently, treatment with pargyline, an inhibitor of both MAO-A and MAO-B, reduced tropomyosin oxidation and led to improvement of the dystrophic phenotype in mdx and col6a1 −/− mice [72].…”

“…Among them, safinamide is a selective and reversible MAO-Bi, with an improved profile of efficacy and safety, that has been introduced in the market for Parkinson’s disease. In a recent report, Safinamide has been shown to markedly improve muscle function in mdx mice, as well as to reduce oxidative stress and mitochondrial dysfunction in muscle cells from DMD patients [56].…”

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

“…Development of novel reversible and selective MAO-B inhibitors with reduced penetration into the CNS is one strategy that has been pursued to reduce CNS and diet-associated side effects (Gealageas et al, 2018). Repurposing of MAO inhibitor drugs is being tested for a variety of non-CNS diseases such as hair growth, ocular disease, muscular dystrophy (Menazza et al, 2010;Vitiello et al, 2018), sexual dysfunction, cardiovascular disease (Deshwal et al, 2017), and cancer (Shih, 2018). New and known coumarins have been synthesized and several have distinct antioxidant and anti-inflammatory effects.…”