Sipatrigine (
BW619C89), a derivative of the
antiepileptic agent lamotrigine, has potent neuroprotective properties in animal models of
cerebral ischemia and
head injury. In the present study we investigated the electrophysiological effects of
sipatrigine utilizing intracellular current-clamp recordings obtained from striatal spiny neurons in rat corticostriatal slices and whole-cell patch-clamp recordings in isolated striatal neurons. The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by
sipatrigine (EC(50) 4.5 microM). Although this
drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first action potentials.
Sipatrigine also inhibited
tetrodotoxin-sensitive
sodium (Na(+)) current recorded from isolated striatal neurons. The EC(50) for this inhibitory action was 7 microM at the holding potential (V(h)) of -65 mV, but 16 microM at V(h) = -105, suggesting a dependence of this pharmacological effect on the membrane potential. Moreover, although the inhibitory action of
sipatrigine on Na(+) currents was maximal during high-frequency activation (20 Hz), it could also be detected at low frequencies. The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by
sipatrigine (EC(50) 2 microM). This inhibitory action, however, was incomplete; in fact maximal concentrations of this
drug reduced EPSP amplitude by only 45%.
Sipatrigine produced no increase in paired-pulse facilitation, suggesting that the modulation of a postsynaptic site was the main pharmacological effect of this agent. The inhibition of voltage-dependent Na(+) channels exerted by
sipatrigine might account for its depressant effects on both repetitive firing discharge and corticostriatal excitatory transmission. The modulation of Na(+) channels described here, as well as the previously observed inhibition of high-voltage-activated
calcium currents, might contribute to the neuroprotective efficacy exerted by this compound in experimental models of in vitro and in vivo
ischemia.