Electrophysiology of sipatrigine: A lamotrigine derivative exhibiting neuroprotective effects

Sipatrigine (BW619C89), a derivative of the antiepileptic agent lamotrigine , has potent neuroprotective properties in animal models of cerebral ischem ia and head injury In the present study we investigated the electrophysiolo gical effects of sipatrigine utilizing intracellular current-clamp recordin gs obtained from striatal spiny neurons in rat corticostriatal slices and w hole-cell patch-clamp recordings in isolated striatal neurons. The number o f action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC50 4.5 mu M). Although this drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first ac tion potentials, Sipatrigne also inhibited tetrodotoxin-sensitive sodium (N a+) current recorded from isolated striatal neurons. The EC50 for this inhi bitory action was 7 mu M at the holding potential (V-h) of -65 mV, but 16 m u M at V-h = -105, suggesting a dependence of this pharmacological effect o n the membrane potential. Moreover, although the inhibitory action of sipat rigine 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 cor ticostriatal pathway, was depressed by sipatrigine (EC50 2 mu M). This inhi bitory action, however, was incomplete; in fact maximal concentrations of t his drug reduced EPSP amplitude by only 45%. Sipatrigine produced no increa se in paired-pulse facilitation, suggesting that the modulation of a postsy naptic site was the main pharmacological effect of this agent, The inhibiti on of voltage-dependent Na+ channels exerted by sipatrigine might account f or its depressant effects on both repetitive firing discharge and corticost riatal excitatory transmission, The modulation of Na+ channels described he re, 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. (C) 2000 Academic Press.