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

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

Publication date: Mar 20, 2020

The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson’s disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNa1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of -120?mV, the half-maximum inhibitory concentrations (IC) were 160 and 33??M at stimulation frequencies of 0.1 and 10?Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420??M for closed channels and 9??M for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of -90?mV and 50-Hz stimulation, safinamide inhibited I with an IC of 6??M, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC of 13??M. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED of 1.2?mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility.

Desaphy, J.F., Farinato, A., Altamura, C., De Bellis, M., Imbrici, P., Tarantino, N., Caccia, C., Melloni, E., Padoani, G., Vailati, S., Keywood, C., Carrat`u, De Luca, A., Conte, D., and Pierno, S. Safinamide’s potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo. 24457. 2020 Exp Neurol.

Concepts Keywords
Action Potential Myotonia warrants
Affinity Disease
Anthracene Branches of biology
Antiarrhythmic Electrophysiology
Anticonvulsant Sodium channel blockers
Carboxylic Acid Integral membrane proteins
Current Clamp Calcium channel blockers
Epilepsy Monoamine oxidase inhibitors
Frequency Safinamide
HEK293T Myotonia
Hz Mexiletine
Intracellular Ion channel
Intraperitoneal Injection Chloride channel blocker
Levodopa
Local Anesthetic
MAOB
Microelectrodes
Muscle
Muscle Fiber
Mutation
Myotonia
Parkinson
Patch Clamp
Receptor
Skeletal Muscle
Sodium
Sodium Channel Blocker
Sodium Channels
Stiffness
Tolerability
Transfected
Vivo
Voltage

Semantics

Type Source Name
drug DRUGBANK Safinamide
disease MESH myotonias
drug DRUGBANK Mexiletine
drug DRUGBANK Levodopa
disease MESH epilepsy
drug DRUGBANK Chloride ion
disease MESH development

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