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
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Search for more papers by this authorSilvia Natoli
Istituto di Anestesia e Rianimazione, Università di Roma “Tor Vergata,” Rome, Italy
Search for more papers by this authorDario Cuomo
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Search for more papers by this authorGiorgio Bernardi
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Fondazione Santa Lucia, I.R.C.C.S.
Search for more papers by this authorPaolo Calabresi
Fondazione Santa Lucia, I.R.C.C.S.
Clinica Neurologica, Università di Perugia, Perugia, Italy
Search for more papers by this authorAntonio Pisani
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Fondazione Santa Lucia, I.R.C.C.S.
Search for more papers by this authorGiuseppina Martella
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Search for more papers by this authorSilvia Natoli
Istituto di Anestesia e Rianimazione, Università di Roma “Tor Vergata,” Rome, Italy
Search for more papers by this authorDario Cuomo
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Search for more papers by this authorGiorgio Bernardi
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Fondazione Santa Lucia, I.R.C.C.S.
Search for more papers by this authorPaolo Calabresi
Fondazione Santa Lucia, I.R.C.C.S.
Clinica Neurologica, Università di Perugia, Perugia, Italy
Search for more papers by this authorAntonio Pisani
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma “Tor Vergata”
Fondazione Santa Lucia, I.R.C.C.S.
Search for more papers by this authorAbstract
Summary: 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 (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.
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