Inhibitory effects of levetiracetam on the high-voltage-activated L-type Ca2+ channels in hippocampal CA3 neurons of spontaneously epileptic rat (SER)

Levetiracetam (LEV) is a widely used antiepileptic agent for partial refractory epilepsy in humans. LEV has unique antiepileptic effects in that it does not inhibit electroshock- or pentylenetetrazol-induced convulsion, but does inhibit seizures in kindling animal and spontaneously epileptic rat (SER: zi/zi, tm/tm) that shows both tonic convulsion and absence-like seizures. LEV also has unique characteristics in terms of its antiepileptic mechanism; it has no activity on Na+ and K+ channels or on glutamate and GABAA receptors. Recently, we found that LEV inhibits the depolarization shift and accompanying repetitive firing induced by mossy fiber stimulation in CA3 neurons of SER hippocampal slices. Therefore, this study was performed to determine whether LEV could inhibit the voltage-activated L-type Ca2+ current of hippocampal CA3 neurons obtained from SER and the non-epileptic Wistar rat. As previously reported, SER CA3 neurons were classified into type 1 and type 2 neurons. The application of LEV (100 μM) elevated the threshold for activation of the Ca2+ current, which was lowered in SER type 1 neurons and reduced the current size. Type 2 neurons of SER have a similar current-voltage relationship to Wistar rat neurons and the decay component of Ca2+ current during depolarization pulse in type 2 neurons was found to be smaller than that in Wistar rat neurons. LEV (100 μM) also reduced Ca2+ current in SER type 2 neurons. The effects of LEV were examined on such type 2 SER hippocampal CA3 neurons, compared with those on Wistar rat CA3 neurons. Application of LEV (10 μM) produced a significant decrease of amplitude of the Ca2+ current in SER neurons, although at this concentration of LEV there was no statistically significant decrease in the amplitude of Ca2+ current in Wistar rat neurons. Furthermore, LEV (100 nM-1 mM) reduced the Ca2+ current in a concentration-dependent manner in both SER and Wistar rat neurons, but the inhibition was much more potent in the former neurons than in the latter. Under the condition that the Ca2+ current had already been inhibited by LEV (10 μM), the addition of nifedipine (10 μM) did not cause further inhibition. Conversely, LEV had no effects on the current that had already been decreased by nifedipine (10 μM) given before LEV treatment (10 μM), indicating that LEV could act on the L-type Ca2+channel. LEV elevated the threshold potential level for activation of the Ca2+ current and reduced the L-type Ca2+ current in type 1 neurons of SER, and the inhibitory action in type 2 neurons was much more potent than that in Wistar rat neurons, suggesting that these effects contribute, at least partly, to the antiepileptic action of LEV.

► Effects of levetiracetam were investigated in hippocampal neurons of spontaneously epileptic rats (SER). ► Levetiracetam inhibits Ca2+ currents in SER hippocampal type 1 and 2 neurons. ► Concentration-dependent inhibition of levetiracetam on Ca2+ currents was more pronounced in SER than in Wistar rats. ► Effects of levetiracetam were on the same L-type Ca2+ channels as nifedipine.