Safinamide's potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo

Desaphy, Jean-François; Farinato, Alessandro; Altamura, Concetta; Bellis, Michela De; Imbrici, Paola; Tarantino, Nancy; Caccia, C.; Melloni, Elsa; Padoani, Gloria; Vailati, Silvia; Keywood, Charlotte; Carratù, Maria Rosaria; Luca, Annamaria De; Conte, Diana; Pierno, Sabata

doi:10.1016/j.expneurol.2020.113287

Cited by 17 publications

(13 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, p.G1306E and p.T1313M were both less sensitive to mexiletine compared to wild-type, but showed unaltered or even increased sensitivity to flecainide and propafenone [65,103]. This offers a great opportunity for exploring other sodium channel blockers ready for repurposing in myotonia [37,[104][105][106][107][108][109][110].…”

Section: Preclinical Studiesmentioning

confidence: 95%

“…Animal models of rare diseases are invaluable tools for a better understanding of the pathogenesis and the discovery of new drugs. Regarding chloride channel myotonia, studies on the genetic models, such as the myotonic goat and adr mouse, and the pharmacologically-induced myotonic rat, have paved the way for human studies [6,38,39,[105][106][107][108][124][125][126][127][128][129][130][131]. Regarding sodium channel myotonia, two mouse models carrying human mutations associated with myotonia and hyperPP are available [132,133].…”

Section: Preclinical Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Desaphy

Altamura

Vicart

et al. 2021

JND

Self Cite

View full text Add to dashboard Cite

Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP. Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background. Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. All steps were performed by two independent investigators, while two others critically reviewed the entire process. Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro, which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from DCP compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies. Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies.

show abstract

Section: Preclinical Studiesmentioning

confidence: 95%

Section: Preclinical Studiesmentioning

confidence: 99%

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Desaphy

Altamura

Vicart

et al. 2021

JND

Self Cite

View full text Add to dashboard Cite

show abstract

“…Resting chloride conductance (gCl), sustained by the muscle ClC-1 channel, controls sarcolemma excitability [17,18]. Indeed, a reduction of ClC-1 channel activity and resting gCl generates myotonic-like symptoms [19][20][21]. Skeletal muscle potassium channels are important for skeletal muscle function since they are involved in cell excitability and metabolism.…”

Section: Pathological Features and Skeletal Muscle Involvementmentioning

confidence: 99%

Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

Tarantino

Canfora

Camerino

et al. 2022

Cells

Self Cite

View full text Add to dashboard Cite

Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.

show abstract

“…Moreover, the antiarrhythmic flecainide and propafenone were proved useful in mexiletine-refractory patients carrying specific SCN4A mutations, suggesting the possibility of defining a mutation-driven pharmacological strategy [ 28 , 29 , 30 , 31 ]. It is feasible to introduce the marketed sodium channel blockers for repurposing myotonia [ 32 , 33 , 34 , 35 ] or developing new derivatives with increased efficacy [ 36 , 37 ].…”

Section: Skeletal Muscle Sodium Channelopathiesmentioning

confidence: 99%

“…The presence of two mutations producing a partial loss of Nav1.4 function leads to congenital myasthenia. A heterozygous null mutation in the SCN4A gene is associated with neonatal hypotonia and congenital myopathy; the concomitance of two null mutations induces neonatal death [ 19 , 33 ]. ACZ has provided some benefits in some patients, but its mechanism of action is still unknown [ 49 , 50 ].…”

Section: Skeletal Muscle Sodium Channelopathiesmentioning

confidence: 99%

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Maggi

Bonanno

Altamura

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.

show abstract

Safinamide's potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo

Cited by 17 publications

References 53 publications

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Contact Info

Product

Resources

About