Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs

Desaphy, Jean-François; Carbonara, Roberta; Costanza, Teresa; Camerino, Diana Conte

doi:10.1016/j.expneurol.2014.02.023

Cited by 47 publications

(64 citation statements)

References 35 publications

(34 reference statements)

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“…48 The most commonly used strategy to treat myotonia is to reduce muscle sodium currents. 28, 48 Our inference that slow inactivation of sodium channels contributes to elimination of myotonia during warm-up suggested that enhancing slow inactivation of sodium channels might offer a more physiologic approach to reducing muscle sodium current. Ranolazine and lacosamide are FDA approved drugs whose mechanism of action is an increase in sodium channel slow inactivation.…”

Section: Discussionmentioning

confidence: 99%

“…The second advantage of using ranolazine may be that it is less likely to induce loss of muscle fiber excitability at high doses. Mexiletine and other sodium channel blockers can readily reduce sodium current to near zero, 28, 49, 51 which induces loss of muscle excitability and weakness. Ranolazine reduces sodium current due to a hyperpolarized shift in the voltage dependence of slow inactivation of channels, but the voltage dependence of Na v 1.4 slow inactivation is shallow such that slow inactivation is almost never complete ( 33, 38 , see however, 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…All mice were tested for baseline motor function before each treatment. Motor function was analyzed by timing the righting reflex 3 times 22, 28 and by scoring 2 performance trials on a modified Rotarod test. In a traditional Rotarod test, mice are placed on a stationary rod and the speed of the rod is gradually increased until the mice can no longer stay on the rod.…”

Section: Methodsmentioning

confidence: 99%

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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Objective Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm up and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warm-up, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warm-up in a mouse model of myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warm-up. These data suggested enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are FDA-approved for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine’s hypoexcitability side effects. Interpretation We conclude ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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“…Mexiletine resulted in greater improvement in stiffness both in human and rat model. 19,20 However, the reason why they are effective only for individual patients and different drugs are all effective for disease caused by the same mutation. For a more precise explanation of mechanism such as ethanol or dantrolene sodium and so on, indeed, a relevant functional study will be needed.…”

Section: Dicussionmentioning

confidence: 99%

Mutations of SCN4A gene cause different diseases: 2 case reports and literature review

Liu

Huang²,

Luan³

et al. 2015

Channels

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“…Hitherto, it was thought that treatments eliminate myotonia via effects on transient Na + channels that lead to elevation of AP threshold 1, 31. Moreover, the previous model did not address termination of myotonia.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting persistent inward sodium currents prevents myotonia

Hawash

Voss

Rich

2017

Annals of Neurology

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ObjectivePatients with myotonia congenita have muscle hyperexcitability due to loss‐of‐function mutations in the ClC‐1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC‐1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC‐1 current.Methods In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.ResultsIntracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin‐sensitive and voltage‐dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.InterpretationThis work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. Ann Neurol 2017;82:385–395

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Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs

Cited by 47 publications

References 35 publications

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Mutations of SCN4A gene cause different diseases: 2 case reports and literature review

Inhibiting persistent inward sodium currents prevents myotonia

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