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 gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 mu M) 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 mu M) consistently inhibited the "persistent" fraction of Na+ currents, whereas even high doses (<= 300 mu M) 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.

Martella, G., De Persis, C., Bonsi, P., Natoli, S., Cuomo, D., Bernardi, G., et al. (2005). Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: Implications for its antiepileptic activity. EPILEPSIA, 46(5), 624-635 [10.1111/j.1528-1167.2005.34904.x].

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

NATOLI, SILVIA;BERNARDI, GIORGIO;PISANI, ANTONIO
2005-01-01

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 (Ca2+) currents from isolated cortical neurons. Results: In bicuculline, to avoid any interference by gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 mu M) 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 mu M) consistently inhibited the "persistent" fraction of Na+ currents, whereas even high doses (<= 300 mu M) 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.
2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/41 - ANESTESIOLOGIA
Settore MED/26 - NEUROLOGIA
English
Con Impact Factor ISI
antiepileptic drugs; cortex; HVA calcium current; paroxysmal depolarizing shift; persistent sodium current; 4 aminobutyric acid A receptor; 4 aminopyridine; bicuculline; calcium channel L type; calcium channel N type; calcium channel P type; calcium channel Q type; magnesium; propofol; sodium; valproic acid; voltage gated calcium channel; action potential; animal cell; animal experiment; animal tissue; anticonvulsant activity; article; brain cell; brain electrophysiology; brain slice; calcium conductance; concentration response; controlled study; depolarization; drug activity; drug effect; drug inhibition; in vitro study; nerve excitability; nonhuman; patch clamp; priority journal; rat; sodium current; action potentials; animals; anticonvulsants; frontal lobe; neocortex; neurons; patch-clamp techniques; pyramidal cells; rats; rats, wistar; sodium channels; status epilepticus; valproic acid
Martella, G., De Persis, C., Bonsi, P., Natoli, S., Cuomo, D., Bernardi, G., et al. (2005). Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: Implications for its antiepileptic activity. EPILEPSIA, 46(5), 624-635 [10.1111/j.1528-1167.2005.34904.x].
Martella, G; De Persis, C; Bonsi, P; Natoli, S; Cuomo, D; Bernardi, G; Calabresi, P; Pisani, A
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Inhibition_of_persistent.pdf

accesso aperto

Licenza: Copyright dell'editore
Dimensione 331.4 kB
Formato Adobe PDF
331.4 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/48125
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 46
  • ???jsp.display-item.citation.isi??? 44
social impact