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

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 long-lasting, 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 (Ca(2+)) currents from isolated cortical neurons.

RESULTS:

In bicuculline, to avoid any interference by gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 microM) 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 (IC(50)), 3.9 microM) consistently inhibited the "persistent" fraction of Na(+) currents, whereas even high doses (< or =300 microM) had negligible effects on the "fast" component of Na(+) currents. HVA Ca(2+) currents were significantly reduced by propofol, and the pharmacologic analysis of this effect showed that propofol selectively reduced L-type HVA Ca(2+) 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 Ca(2+) 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.

• Authors: Giuseppina Martella, Cristiano De Persis, Paola Bonsi, Silvia Natoli, Dario Cuomo, Giorgio Bernardi, Paolo Calabresi, Antonio Pisani
• Journal: Epilepsia (Epilepsia) Vol. 46 Issue 5 Pg. 624-35 (May 2005) ISSN: 0013-9580 [Print] United States
• PMID: 15857426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Calcium Channels, L-Type
• Sodium Channels
• Valproic Acid
• Sodium
• Propofol

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Anticonvulsants (pharmacology)
• Calcium Channels, L-Type (drug effects, metabolism)
• Frontal Lobe (cytology, drug effects, metabolism)
• In Vitro Techniques
• Neocortex (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Patch-Clamp Techniques
• Propofol (pharmacology)
• Pyramidal Cells (drug effects, metabolism)
• Rats
• Rats, Wistar
• Sodium (physiology)
• Sodium Channels (drug effects, metabolism)
• Status Epilepticus (prevention & control)
• Valproic Acid (pharmacology)