Inhibition of Persistent Sodium Current Fraction and Voltage‐gated L‐type Calcium Current by Propofol in Cortical Neurons: Implications for Its Antiepileptic Activity

Abstract

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 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 (Ca 2+ ) 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 (IC 50 ), 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 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-Agated chloride channels, to achieve depression of cortical activity during both anesthesia and status epilepticus.

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Latency of ST-EPSCs was unaffected by 30 µM propofol. In contrast, in cortical neurons, sodium channels, spiking and nerve conduction are inhibited by low micromolar propofol concentrations (Rehberg & Duch, 1999;Bieda & MacIver, 2004;Martella et al, 2005;Jones et al, 2007). We conclude that the afferent axon and terminal excitation process is remarkably insensitive to propofol and this may reflect the expression of a particular complement of ion channels within peripheral afferent neuron axons (Schild et al, 1994;Schild & Kunze, 1995).…”

“…Thus, on average, the mean amplitude of the first evoked ST-EPSC (ST-EPSC 1 ) remained unchanged from control up to the highest concentration tested propofol (30 µM, Figure 5B). Although in cortical neurons sodium channels, spiking and nerve conduction are inhibited by low micromolar propofol concentrations (Rehberg & Duch, 1999;Bieda & MacIver, 2004;Martella et al, 2005;Jones et al, 2007), ST-EPSC latency remained constant during propofol (p=0.958, n=5, Figure 5C), a finding that suggests that sensory axon conduction and glutamate release are unimpeded by the anesthetic. Likewise, following pharmacological isolation of sEPSCs with gabazine, propofol did not alter decay-time constants, amplitudes, frequencies or the holding current at any concentration tested (n=6, Figure 5D).…”

The Action Sites of Propofol in the Normal Human Brain Revealed by Functional Magnetic Resonance Imaging

“…Our previous study showed that in healthy volunteers, propofol significantly influenced release of these neurotransmitters, in different brain regions (Zhang et al, 2009). Furthermore, it is reported that propofol could modulate the function of sodium and calcium channels (Martella et al, 2005) and endocannabinoid system (Guindon et al, 2007). However, in the intact central nervous system (CNS), especially in human beings during anesthesia, the functional target of propofol is still a mystery.…”

Hydroxyamide Analogs of Propofol Exhibit State-Dependent Block of Sodium Channels in Hippocampal Neurons: Implications for Anticonvulsant Activity

“…general anesthetic; however, at subanesthetic doses, propofol is used clinically during refractory status epilepticus, a critical medical emergency with mortality rates as high as 76% in elderly patients (Prasad et al, 2001;Claassen et al, 2002;Marik and Varon, 2004;Rossetti et al, 2004). Propofol has been shown to inhibit sodium currents in mammalian cell lines expressing rat Na v 1.2 (Rehberg and Duch, 1999), to activate GABA currents in hippocampal neurons (Orser et al, 1994), and to inhibit L-type calcium currents in cortical neurons (Martella et al, 2005). However, its modulation of sodium currents (Martella et al, 2005) has been suggested to be important for its AED activity in both veratridine-induced seizures (Otoom and Hasan, 2004) and amygdala-kindled rats (Borowicz and Czuczwar, 2003).…”

“…Propofol has been shown to inhibit sodium currents in mammalian cell lines expressing rat Na v 1.2 (Rehberg and Duch, 1999), to activate GABA currents in hippocampal neurons (Orser et al, 1994), and to inhibit L-type calcium currents in cortical neurons (Martella et al, 2005). However, its modulation of sodium currents (Martella et al, 2005) has been suggested to be important for its AED activity in both veratridine-induced seizures (Otoom and Hasan, 2004) and amygdala-kindled rats (Borowicz and Czuczwar, 2003). Although the mechanisms of action for propofol remain unclear, it continues to be an effective alternative to barbiturates and first line AEDs when treating refractory status epilepticus (Rossetti et al, 2004).…”