期刊
EPILEPSIA
卷 46, 期 5, 页码 624-635出版社
WILEY
DOI: 10.1111/j.1528-1167.2005.34904.x
关键词
cortex; antiepileptic drugs; paroxysmal depolarizing shift; HVA calcium current; persistent sodium current
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.
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