Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current

Background: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys_(V)] of ionic currents remains unknown. Methods: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na_V) channels in pituitary GH3 cells. Results: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (I_Na) in pituitary GH₃ cells. The conductance–voltage relationship of transient I_Na [I_Na(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I_Na(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I_Na(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window I_Na induced by an ascending ramp voltage V_ramp. Furthermore, SAF enhanced the Hys_(V) behavior of persistent I_Na induced by an upright isosceles-triangular V_ramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na_V channels. Molecular docking revealed SAF interacts with both MAO and Na_V channels. Conclusion: SAF may interact directly with Na_V channels in pituitary neuroendocrine cells, modulating membrane excitability.