Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: Implications for its antiepileptic activity

Giuseppina Martella, Cristiano De Persis, Paola Bonsi, Silvia Natoli, Dario Cuomo, Giorgio Bernardi, Paolo Calabresi, Antonio Pisani

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Although it is widely used in clinical practice, the mechanisms of action of 2,6-di-isopropylphenol (propofol) are not completely understood. We examined the electrophysiologic effects of propofol on an in vitro model of epileptic activity obtained from a slice preparation. Methods: The effects of propofol were tested both on membrane properties and on epileptiform events consisting of longlasting, paroxysmal depolarization shifts (PDSs) induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine.These results were integrated with a patch-clamp analysis of Na+ and high-voltage activated (HVA) calcium (Ca2+) currents from isolated cortical neurons. Results: In bicuculline, to avoid any interference by γ-aminobutyric acid (GABA)-A receptors, propofol (3-100 μM) did not cause significant changes in the current-evoked, sodium (Na +)-dependent action-potential discharge. However, propofol reduced both the duration and the number of spikes of PDSs recorded from cortical neurons. Interestingly, relatively low concentrations of propofol [half-maximal inhibitory concentration (IC50), 3.9 μM) consistently inhibited the "persistent" fraction of Na+ currents, whereas even high doses (≤300 μM) had negligible effects on the "fast" component of Na+ currents. HVA Ca2+ currents were significantly reduced by propofol, and the pharmacologic analysis of this effect showed that propofol selectively reduced L-type HVA Ca2+ currents, without affecting N or P/Q-type channels. Conclusions: These results suggest that propofol modulates neuronal excitability by selectively suppressing persistent Na+ currents and L-type HVA Ca2+ conductances in cortical neurons. These effects might cooperate with the opening of GABA-A-gated chloride channels, to achieve depression of cortical activity during both anesthesia and status epilepticus.

Original languageEnglish
Pages (from-to)624-635
Number of pages12
JournalEpilepsia
Volume46
Issue number5
DOIs
Publication statusPublished - May 2005

Keywords

  • Antiepileptic drugs
  • Cortex
  • HVA calcium current
  • Paroxysmal depolarizing shift
  • Persistent sodium current

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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