The Novel Direct Modulatory Effects of Perampanel, an Antagonist of AMPA Receptors, on Voltage-Gated Sodium and M-type Potassium Currents

Abstract

Perampanel (PER) is a selective blocker of AMPA receptors showing efficacy in treating various epileptic disorders including brain tumor-related epilepsy and also potential in treating motor neuron disease. However, besides its inhibition of AMPA-induced currents, whether PER has any other direct ionic effects in different types of neurons remains largely unknown. We investigated the effects of PER and related compounds on ionic currents in different types of cells, including hippocampal mHippoE-14 neurons, motor neuron-like NSC-34 cells and U87 glioma cells. We found that PER differentially and effectively suppressed the amplitude of voltage-gated Na+ currents (INa) in mHippoE-14 cells. The IC50 values required to inhibit peak and late INa were 4.12 and 0.78 μM, respectively. PER attenuated tefluthrin-induced increases in both amplitude and deactivating time constant of INa. Importantly, PER also inhibited the amplitude of M-type K+ currents (IK(M)) with an IC50 value of 0.92 μM. The suppression of IK(M) was attenuated by the addition of flupirtine or ZnCl2 but not by L-quisqualic acid or sorafenib. Meanwhile, in cell-attached configuration, PER (3 μM) decreased the activity of M-type K+ channels with no change in single-channel conductance but shifting the activation curve along the voltage axis in a rightward direction. Supportively, PER suppressed IK(M) in NSC-34 cells and INa in U87 glioma cells. The inhibitory effects of PER on both INa and IK(M), independent of its antagonistic effect on AMPA receptors, may be responsible for its wide-spectrum of effects observed in neurological clinical practice.

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

“…It should be noticed that the neurological or cardioprotective actions caused by SSM, SesA, or other structurally similar compounds, as described previously [42,[46][47][48][49][50][51][52][53], can be intimately linked to their direct actions on the amplitude and gating of ion currents (e.g., I Na ). Similar to the ranolazine or perampanel action on I Na described previously [23,25], the inhibitory effect of SSM on ion currents seen herein may be responsible for its wide spectrum of effects observed in vivo [3,54]. Additionally, caution needs to be taken in the interpretation of sesame oil as a fat-soluble vehicle [55][56][57].…”

“…Nine isoforms (Na V 1.1-1.9) are found in mammalian excitable tissues, including the central nervous system, peripheral nervous system, endocrine system, skeletal muscles, and heart [22]. Moreover, several inhibitors known to preferentially block the late component of voltage-gated Na+ currents (I Na ), such as ranolazine, eugenol, and perampanel, have been reported to suppress seizure activity [23][24][25]. However, whether SSM or SesA are capable of exerting any perturbation on the amplitude and gating of I Na in response to rapid membrane depolarization remains poorly understood, though SSM was previously noted to activate transient receptor potential vanilloid type 1 in endothelial cells [26].…”

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

“…However, in the continued presence of 3 µM CIL, subsequent application of 3 µM A-803467 or 3 µM tefluthrin to the bath medium was able to suppress or enhance the peak I Na density, respectively. A-803467 has been reported to be a selective blocker of Na V 1.8 channels [31], while tefluthrin, a pyrethroid, can activate I Na [32]. Similarly, further addition of 1 µM tetrodotoxin, still in the presence of 3 µM CIL, was found to fully decreased peak I Na density.…”

Depressive Effectiveness of Vigabatrin (y-Vinyl-GABA), an Antiepileptic Drug, in Intermediate-conductance Calcium-Activated Potassium Channels in Human Glioma Cells

“…The composition of the bathing solution (i.e., HEPES-buffered normal Tyrode's solution) was 136.5 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl 2 , 0.53 mM MgCl 2 , 5.5 mM glucose, and 5.5 mM HEPES titrated with NaOH to pH 7.4. To measure K + currents, we back lled the patch pipettes with an internal solution consisting of 130 mM K-aspartate, 20 mM KCl, 1 mM KH 2 PO 4 , 1 mM MgCl 2 , 3 mM Na 2 ATP, 100 μM Na 2 GTP, 0.1 mM EGTA, and 5 mM HEPES adjusted with KOH to pH 7.2 [18,19]. To avoid the contamination of whole-cell Clcurrents, we replaced Clions inside the pipette solution with aspartate.…”