Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (Kv3.1): Contribution to the firing of action potentials

Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the K_V3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K⁺ current (I_K(DR)) in a concentration-dependent manner with an IC ₅₀ value of 37 μM. LEV (30 μM) shifted the steady-state activation of I_K(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of I_K(DR). Neither Na ⁺, nor erg (ether-a-go-go-related)-mediated K⁺ and ATP-sensitive K⁺ currents were affected by LEV (100 μM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating I_K(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating I_K(DR) (K_V3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.