Abstract
Lacosamide (Vimpat®, LCS) is widely known as a functionalized amino acid with promising anti-convulsant properties; however, adverse events during its use have gradually appeared. Despite its inhibitory effect on voltage-gated Na+ current (INa), the modifications on varying types of ionic currents caused by this drug remain largely unexplored. In pituitary tumor (GH3) cells, we found that the presence of LCS concentration-dependently decreased the amplitude of A-type K+ current (IK(A)) elicited in response to membrane depolarization. The IK(A) amplitude in these cells was sensitive to attenuation by the application of 4-aminopyridine, 4-aminopyridine-3-methanol, or capsaicin but not by that of tetraethylammonium chloride. The effective IC50 value required for its reduction in peak or sustained IK(A) was calculated to be 102 or 42 µM, respectively, while the value of the dissociation constant (KD) estimated from the slow component in IK(A) inactivation at varying LCS concentrations was 52 µM. By use of two-step voltage protocol, the presence of this drug resulted in a rightward shift in the steady-state inactivation curve of IK(A) as well as in a slowing in the recovery time course of the current block; however, no change in the gating charge of the inactivation curve was detected in its presence. Moreover, the LCS addition led to an attenuation in the degree of voltage-dependent hysteresis for IK(A) elicitation by long-duration triangular ramp voltage commands. Likewise, the IK(A) identified in mouse mHippoE-14 neurons was also sensitive to block by LCS, coincident with an elevation in the current inactivation rate. Collectively, apart from its canonical action on INa inhibition, LCS was effective at altering the amplitude, gating, and hysteresis of IK(A) in excitable cells. The modulatory actions on IK(A), caused by LCS, could interfere with the functional activities of electrically excitable cells (e.g., pituitary tumor cells or hippocampal neurons).
Highlights
IntroductionOf note, LCS is safe and effective in anti-convulsant activities, the unwanted events following LCS treatment, such as dizziness, abnormal vision, diplopia, ataxia, personality changes, and cardiovascular adverse events (e.g., sinus node dysfunction), have gradually emerged [3,6,7,18,19,20,21,22,23,24]
In light of the above-mentioned considerations, the objective of the current study is to address the question of whether LCS can cause any possible modifications on other types of membrane ionic currents, such as IK(A) in pituitary tumor (GH3 ) cells and mHippoE-14 hippocampal neurons, and to determine the gating kinetics of IK(A) in the presence of LCS and to evaluate whether LCS interferes with the strength of voltagedependent hysteresis (Vhys ) of IK(A) activated by isosceles-triangular ramp pulse
We found that the presence of LCS could depress IK(A) in a concentration, time, state, and hysteresis-dependent manner in GH3 cells
Summary
Of note, LCS is safe and effective in anti-convulsant activities, the unwanted events following LCS treatment, such as dizziness, abnormal vision, diplopia, ataxia, personality changes, and cardiovascular adverse events (e.g., sinus node dysfunction), have gradually emerged [3,6,7,18,19,20,21,22,23,24]. The risk of myoclonic seizure was reported to occur during the treatment with this drug [25]. A previous report by Hagenacker et al (2013) has shown the ability of LCS to reduce analgesic effects and limit the effect on INa inhibition in dorsal root ganglion neurons in a model of peripheral neuropathic pain [26]. It is worthwhile to reappraise the ionic mechanism of LCS actions in varying types of transmembrane ionic currents, the voltage-gated Na+ (NaV ) channels were, until recently, focused on its therapeutic effectiveness [27,28,29,30,31,32]
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