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 hNav1.4
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 (IC50) were 160 and 33 μM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of
safinamide were dependent on channel state: 420 μM for closed channels and 9 μM 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 INa with an IC50 of 6 μM, 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 IC50 of 13 μM. 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 ED50 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.