The Integrated Effects of Brivaracetam, a Selective Analog of Levetiracetam, on Ionic Currents and Neuronal Excitability

Abstract

Brivaracetam (BRV) is recognized as a novel third-generation antiepileptic drug approved for the treatment of epilepsy. Emerging evidence has demonstrated that it has potentially better efficacy and tolerability than its analog, Levetiracetam (LEV). This, however, cannot be explained by their common synaptic vesicle-binding mechanism. Whether BRV can affect different ionic currents and concert these effects to alter neuronal excitability remains unclear. With the aid of patch clamp technology, we found that BRV concentration dependently inhibited the depolarization-induced M-type K+ current (IK(M)), decreased the delayed-rectifier K+ current (IK(DR)), and decreased the hyperpolarization-activated cation current in GH3 neurons. However, it had a concentration-dependent inhibition on voltage-gated Na+ current (INa). Under an inside-out patch configuration, a bath application of BRV increased the open probability of large-conductance Ca2+-activated K+ channels. Furthermore, in mHippoE-14 hippocampal neurons, the whole-cell INa was effectively depressed by BRV. In simulated modeling of hippocampal neurons, BRV was observed to reduce the firing of the action potentials (APs) concurrently with decreases in the AP amplitude. In animal models, BRV ameliorated acute seizures in both OD-1 and lithium-pilocarpine epilepsy models. However, LEV had effects in the latter only. Collectively, our study demonstrated BRV’s multiple ionic mechanism in electrically excitable cells and a potential concerted effect on neuronal excitability and hyperexcitability disorders.

Synaptic Vesicle Glycoprotein 2A: Features and Functions

“…It is unclear how levetiracetam improves the epileptic phenotype upon SV2A binding, and a number of levetiracetam derivatives that maintain SV2A selective targeting and eventually have higher pharmacological effects are under scrutiny. In particular, brivaracetam is the main levetiracetam analog, with significant effects on neuronal excitability possibly due to multiple ionic mechanisms ( Hung et al, 2021 ).…”

Characterization in Effective Stimulation on the Magnitude, Gating, Frequency Dependence, and Hysteresis of INa Exerted by Picaridin (or Icaridin), a Known Insect Repellent

“…Moreover, upon continued presence of 10 μM picaridin, a further application of brivaracetam (BRV, 10 μM) noticeably attenuated the picaridin-prolonged time constant of I Na(T) inactivation during repetitive depolarizations to 41.1 ± 2.6 ms (n = 7, p < 0.05). BRV was recently reported to suppress I Na(T) amplitude [ 43 ]. Overall, these results meant that, apart from the increase in I Na(T) amplitude, with cell exposure to picaridin the decrease in the decaying of I Na(T) in response to a 1-s train of depolarizing pulses (i.e., accumulative inactivation of I Na(T) ) could become retarded in these cells.…”

Zingerone Modulates Neuronal Voltage-Gated Na+ and L-Type Ca2+ Currents

“…GH 3 pituitary cells were acquired from the Bioresources Collection and Research Center (BCRC-60015; Hsinchu, Taiwan), whereas the embryonic mouse hippocampal cell line (mHippoE-14; CLU198) was obtained from CELLutions Biosystems (Cedarlane ® ; Burlington, ON, Canada). The GH 3 cells were maintained and subcultured in Ham’s F-12 media supplemented with 15% horse serum ( v/v ), 2.5% fetal calf serum ( v/v ), and 2 mM of L-glutamine [ 41 , 42 ], and the mHippoE-14 cells were maintained in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum ( v/v ) and 2 mM of L-glutamine [ 43 ]. Under our experimental conditions, the cell viability remained at 80–90% for at least two weeks.…”