Electrophysiology of sipatrigine: A lamotrigine derivative exhibiting neuroprotective effects

Paolo Calabresi, Alessandro Stefani, Girolama A. Marfia, Atticus H. Hainsworth, Diego Centonze, Emilia Saulle, Francesca Spadoni, Michael J. Leach, Patrizia Giacomini, Giorgio Bernardi

Research output: Contribution to journalArticlepeer-review

Abstract

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 (EC50 4.5 μM). 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 EC50 for this inhibitory action was 7 μM at the holding potential (V(h)) of -65 mV, but 16 μM 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 (EC50 2 μM). 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. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)171-179
Number of pages9
JournalExperimental Neurology
Volume162
Issue number1
DOIs
Publication statusPublished - Mar 2000

Keywords

  • Antiepileptic drugs
  • Neuroprotective drugs
  • Sodium currents
  • Stroke
  • Synaptic potentials

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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