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Anesth Analg 2004;99:1095-1101
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130356.22414.2B

ANESTHETIC PHARMACOLOGY

The Anticonvulsant Action of Propofol on Epileptiform Activity in Rat Hippocampal Slices

Hideya Ohmori, MD*, Yasumitsu Sato, MD PhD{dagger}, and Akiyoshi Namiki, MD PhD{ddagger}

*Department of Anesthesiology, Kitami Red Cross Hospital; {dagger}Department of Anesthesiology, Moriyama Hospital; and {ddagger}Department of Anesthesiology, Sapporo Medical University School of Medicine, Hokkaido, Japan

Address correspondence and reprint requests to Yasumitsu Sato, Department of Anesthesiology, Moriyama Hospital, 8-6 Asahikawa, Hokkaido, 070-0038 Japan. Address e-mail to ymsato{at}d5.dion.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We used extracellular electrophysiological recordings from the CA1 region in rat hippocampal slices to investigate the effects of propofol on the field excitatory postsynaptic potential (fEPSP), population spike, and epileptiform activity induced by a Mg2+-free condition. Propofol depressed the population spike, fEPSP, and epileptiform activity. Both aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine, an A1 receptor antagonist, significantly reduced the effect of propofol on fEPSP amplitude. However, 3,7-dimethyl-1-propagylxanthine, an A2 receptor antagonist, did not alter the effect of propofol on fEPSP amplitude. Picrotoxin, a specific chloride channel blocker, partly reduced the effect of propofol on epileptiform activity, but bicuculline, a competitive {gamma}-aminobutyric acidA receptor antagonist, failed to antagonize it. Aminophylline significantly reduced the action of propofol on the epileptiform activity. The anticonvulsant action of propofol was partly reduced by 8-cyclopentyl-1,3-dipropylxanthine, whereas 3,7-dimethyl-1-propagylxanthine failed to affect it. Adenosine depressed the amplitude of fEPSPs in a dose-dependent manner, and propofol enhanced this inhibition. The results demonstrated that, in rat hippocampal slices, propofol inhibits epileptiform activity. In addition, adenosine neuromodulation through the A1 receptor may contribute to the anticonvulsant action of propofol.

IMPLICATIONS: We have demonstrated that propofol depressed epileptiform activity in rat hippocampal slices. Adenosine neuromodulation through the A1 receptor may contribute to the anticonvulsant action of propofol.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Propofol is an IV anesthetic that may have both pro- and anticonvulsant actions in vivo. An increase in the mean spike number and an extension of spike distribution in the electrocorticogram after propofol administration were observed in patients with seizure disorders (1,2). In contrast, propofol was used successfully in the treatment of status epilepticus (3) and has been reported to decrease the duration of seizure activity during electroconvulsive therapy (4). Numerous animal studies have shown that propofol possesses anticonvulsant properties against seizures induced by electroshock (5), bupivacaine (6), and some chemoconvulsants (7). An anticonvulsant action of propofol is supported by electrophysiological studies, which have demonstrated that propofol enhances inhibitory {gamma}-aminobutyric acid (GABA)A receptor-mediated responses and directly activates GABAA receptors (8,9). There is clinical (10) and experimental (11) evidence that adenosinergic neurotransmission can modulate certain types of seizures. Anticonvulsant effects have been reported after activation of the adenosine system with an adenosine A1 receptor agonist (12). However, an electrophysiological study of the interaction of propofol with the adenosine system has not been reported. In the present study, we investigated the contribution of adenosine neuromodulation to propofol-induced depression of excitatory synaptic transmission.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All of the experimental procedures used in this study were reviewed and approved by the animal care and use committee of our institute.

All of the experiments used the CA1 region in hippocampal brain slices prepared from 3- to 6-wk-old Sprague-Dawley rats (80–150 g, of either sex). The rats were anesthetized with isoflurane and then decapitated. The brain was rapidly removed and placed in a cold (3°C–4°C), oxygenated, and sucrose-based artificial cerebrospinal fluid (ACSF). The constituents of the sucrose-based ACSF were (in mM): sucrose 220, KCl 3.0, MgSO4 2.0, NaH2PO4 1.25, NaHCO3 26, CaCl2 2.0, and glucose 10. The brain was immersed in oxygenated sucrose-based ACSF, and while immersed, slices were cut with a vibrating tissue slicer (DTK-3000; Dosaka EM, Kyoto, Japan). The brain slices, each 350-µm thick, were immediately transferred to a holding chamber filled with normal ACSF through which a gas mixture of 95% O2/5% CO2 was bubbled. The constituents of the normal ACSF were (in mM): NaCl 124, KCl 5.0, MgSO4 2.0, NaH2PO4 1.25, CaCl2 2.0, NaHCO3 22, and glucose 10. After an incubation period of 1 h, a single brain slice was transferred to a submerged recording chamber. In the recording chamber, the brain slice was continuously perfused with oxygenated and warmed normal ACSF (32°C ± 1°C; pH value of 7.4).

A bipolar stimulating electrode was placed in the region of the stratum radiatum to activate the Schaffer-collateral commissural fibers. Tungsten microelectrodes (2–4 M{Omega}) were placed in the region of the cell bodies of the CA1 pyramidal neurons and the stratum radiatum to record population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs), respectively. Single or paired pulses (pulse width, 0.2 m; frequency, 0.17 Hz) from a SEN-7203 stimulator (Nihon Kohden, Tokyo, Japan) were delivered to the preparation through an SS-102J isolation unit (Nihon Kohden). The interstimulus intervals of paired stimuli varied from 10 to 60 ms. The stimulus intensity (0.3–1.0 mA) was adjusted for each experiment to yield fEPSPs or PSs that were 75% of the maximal responses. The epileptiform activity was induced by omitting MgSO4 from the ACSF. The evoked responses were amplified using a DAM 5A-A amplifier (World Precision Instruments, New Haven, CT) with a low frequency cutoff of 1 Hz and a high frequency cutoff of 30 kHz. The frequency of analog to digital conversion was 20 kHz, and all of the data were stored on a hard disk of a Macintosh computer for later analysis.

For computer analysis of the data, groups of five individual responses were averaged and stored as a single record. The amplitude of each fEPSP was measured as the peak negativity from the baseline. The amplitude of each PS measurement was as follows. Briefly, a sloping baseline was drawn between the two upward peaks, and the amplitude of the PS was calculated as the length of a vertical line drawn from the downward peak to the sloping baseline. The effect of propofol on the epileptiform activity was evaluated on the amplitude of the first, second, and third PSs and on the duration of the spike discharges. The duration was measured from the first to the last PS with an amplitude more than 0.2 mV. All of the responses were normalized as a percentage of the control.

Propofol, (-) bicuculline methiodide, picrotoxin, aminophylline, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 3,7-dimethyl-1-propagylxanthine (DMPX) were obtained from Research Biochemicals (Natick, MA). Adenosine was obtained from Sigma (St Louis, MO). All of the drugs were applied to the slices extracellularly through the superfusing ACSF. Because propofol, DPCPX, and DMPX are sparingly soluble in aqueous solutions, dimethyl sulfoxide was added. A pilot study confirmed that dimethyl sulfoxide at the largest possible concentration of 0.2% did not have detectable effects on the fEPSP and PS amplitude.

All data are expressed as mean ± SD. The statistical significance of any difference in data from the two groups was determined by using Student’s t-test (unpaired). The dose-response effects of propofol on the PS amplitude and duration were assessed using a one-way analysis of variance with repeated measures and Scheffe post hoc test. Any differences were considered to be significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
We first investigated the effects of propofol on PSs and fEPSP in normal ACSF. Figure 1A shows representative recordings of the effects of 1 µM of propofol on the PSs. The first PS amplitude was decreased by 1 µM of propofol to 58.0% ± 18.9% of control (n = 7). Figure 1A also illustrates that paired pulse inhibition (PPI) was observed in the presence of propofol when the interstimulus interval (ISI) was 30 ms. The PS2/PS1 ratios at ISIs of 10 ms, 30 ms, and 60 ms were 0.87 ± 0.39, 1.03 ± 0.13, and 1.17 ± 0.26, respectively (Fig. 1B; n = 7). Propofol prolonged the period of PPI. In the presence of 1 µM of propofol, the PS2/PS1 ratios at ISIs of 10 ms, 30 ms, and 60 ms were 0.48 ± 0.26, 0.75 ± 0.17, and 0.80 ± 0.22, respectively (n = 7; P < 0.05, compared with the control). The fEPSP was also depressed by propofol. Representative recordings of the effects of 1 µM of propofol on fEPSP are shown in Figure 2A. Propofol 1 µM decreased fEPSP amplitude to 65.4% ± 28.4% (Fig. 2B; n = 10). The influence of adenosine antagonists on propofol-induced fEPSP depression was investigated. The depression of fEPSP that was produced by 1 µM of propofol was significantly antagonized by a nonselective adenosine receptor antagonist, aminophylline, and an A1 receptor antagonist, DPCPX (Fig. 2B). In contrast, an A2 receptor antagonist, DMPX, did not alter the effect on the action of 1 µM of propofol on fEPSP amplitude (Fig. 2B).


Figure 1
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  		Figure 1. (A) An example of the effect of 1 µM of propofol on population spikes (PSs) in normal artificial cerebrospinal fluid. PSs were elicited with a paired-pulse stimulus. (B) The effects of 1 µM of propofol on PS2/PS1 ratios at various interstimulus intervals. Data are expressed as mean ± SD (n = 7; *P < 0.05 compared with control, unpaired t-test).

 

Figure 2
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  		Figure 2. (A) An example of the effect of 1 µM of propofol on field excitatory postsynaptic potentials (fEPSPs) in normal artificial cerebrospinal fluid. The fEPSP was elicited with a single stimulus. (B) The effects of 1 µM of propofol on fEPSP amplitudes in normal artificial cerebrospinal fluid (n = 10) and in slices pretreated with 100 µM of aminophylline, 0.4 µM of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or 10 µM of 3,7-dimethyl-1-propagylxanthine (DMPX). Propofol 1 µM depressed fEPSPs in slices pretreated with 100 µM of aminophylline, 0.4 µM of DPCPX, and 10 µM of DMPX; i.e., the fEPSP amplitude was decreased by propofol to 85.1% ± 5.8% (n = 10), 88.3% ± 9.6% (n = 10), and 71.1% ± 18.5% (n = 10), respectively. P = propofol, P + A = propofol + aminophylline, P + DC = propofol + DPCPX, P + DM = propofol + DMPX. *P < 0.05.

 
Next, we investigated the effects of propofol on epileptiform activity. Representative recordings of the effects of 1 µM of propofol on epileptiform activity induced by Mg2+-free ACSF are shown in Figure 3A. Propofol 1 µM decreased the amplitude of the first PS, second PS, and third PS to 52.6% ± 21.5%, 42.2% ± 29.9%, and 31.8% ± 27.9%, respectively (n = 8). The concentration-effect relationship between propofol (0.1, 1, 10, and 100 µM) and PSs amplitude is summarized in Figure 3B. The duration of the spike discharge was reduced by 1 µM of propofol to 75.7% ± 12.7% of control (n = 8). The concentration-effect relationship of 4 concentrations of propofol (0.1, 1, 10, and 100 µM) and the duration of the spike discharge are shown in Figure 3C.


Figure 3
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  		Figure 3. Propofol depressed epileptiform activity induced by Mg2+-free conditions. (A) Representative response of the effect of 1 µM of propofol on epileptiform activity. (B) Concentration-response relationship for propofol on the amplitude of the first, second, and third population spike (PS). Propofol produced an inhibitory effect on PS amplitude in a concentration-dependent manner (n = 6 for 0.1 µM of propofol; n = 8 for the other concentrations; *P < 0.05, analysis of variance). (C) Propofol decreased the duration of epileptiform activity in a dose-dependent manner (n = 6 for 0.1 µM of propofol; n = 8 for the other concentrations; *P < 0.05, analysis of variance).

 
Bicuculline, a competitive GABAA receptor antagonist, did not antagonize the effect of 1 µM of propofol on epileptiform activity. In the presence of 30 µM of bicuculline, the amplitude of the first, second, and third PS was decreased by 1 µM of propofol to 56.3% ± 20.5%, 48.8% ± 19.7%, and 47.4% ± 15.8%, respectively (n = 8). The duration of the spike discharge was reduced to 76.8% ± 12.3% of the control (n = 8). Picrotoxin, a specific chloride channel blocker, partly antagonized the effect of 1 µM of propofol on epileptiform activity. The amplitude of the first, second, and third PS was decreased by 1 µM of propofol to 78.4% ± 15.4%, 60.9% ± 26.5%, and 63.0% ± 30.0%, respectively (n = 7). The only significant difference was between the amplitudes of the first PS (P < 0.05, when compared with propofol alone). The duration of the spike discharge was reduced to 81.4% ± 19.6% of control.

The depression of epileptiform activity caused by 1 µM of propofol was significantly antagonized by aminophylline. Typical records, presented in Figure 4A, show the effects of 1 µM of propofol on epileptiform activity induced by Mg2+-free ACSF containing 100 µM of aminophylline. The amplitude of the first, second, and third PS decreased to 78.9% ± 12.6%, 66.9% ± 15.6%, and 67.6% ± 25.8%, respectively (Fig. 4B; n = 8; P < 0.05, when compared with propofol alone). The duration of the spike discharge was decreased to 92.6% ± 17.6% of control (Fig. 4C; n = 8; P < 0.05). The action of 1 µM of propofol on the epileptiform activity was partly antagonized by DPCPX. Propofol 1 µM decreased the amplitude of the first, second, and third PS to 74.3% ± 13.0%, 46.9% ± 25.5%, and 41.2% ± 32.9%, respectively (n = 7). A significant difference only occurred between the amplitudes of the first PS (P < 0.05, when compared with propofol alone). The spike discharge duration was reduced to 77.95 ± 19.1% of control (n = 7). The effect of 1 µM of propofol on epileptiform activity was not antagonized by DMPX. The amplitude of the first, second, and third PS was decreased by 1 µM of propofol to 57.1% ± 25.8%, 46.2% ± 29.1%, and 38.4% ± 27.0%, respectively (n = 7), in the presence of 10 µM of DMPX. The spike discharge duration was reduced to 72.7% ± 22.5% of control (n = 7).


Figure 4
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  		Figure 4. (A) Representative response of the effect of 1 µM of propofol on epileptiform activity in the presence of 100 µM of aminophylline. (B) A nonselective adenosine receptor antagonist, aminophylline, antagonized the effect of 1 µM of propofol on the amplitude of the epileptiform activity. (n = 8; *P < 0.05 compared with the control, unpaired t-test). (C) The effect of 1 µM of propofol on the duration of the epileptiform discharges was antagonized with 100 µM of aminophylline (n = 8; *P < 0.05). PS = population spike.

 
To investigate the interaction of propofol with the adenosine system, we constructed concentration-response relationships for exogenously applied adenosine in the absence and presence of propofol. Figure 5A shows the concentration-related inhibition of fEPSP amplitude by adenosine and the enhancement of this inhibition by 1 µM of propofol. A summary of the data is shown in Figure 5B. The fEPSP amplitude was decreased to 88.8% ± 8.7% of the control by 1 µM of adenosine, to 59.6% ± 12.0% of control by 10 µM of adenosine, and to 16.3% ± 14.0% of control by 100 µM of adenosine (Fig. 5B; n = 7). In the presence of propofol 1 µM, after the evoked fEPSP had stabilized, 3 different concentrations of adenosine were applied. In the propofol-pretreated slices, all of the responses after adenosine were normalized as a percentage of the postpropofol control value. In the presence of 1 µM of propofol, the fEPSP amplitude was decreased to 66.4% ± 19.9% of control by 1 µM of adenosine (n = 7; P < 0.05). The amplitude was also decreased to 41.0% ± 16.0% of the control by 10 µM of adenosine (n = 7; P < 0.05) and to 23.0% ± 17.7% of control by 100 µM of adenosine (n = 7).


Figure 5
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  		Figure 5. (A) Inhibition of field excitatory postsynaptic potentials (fEPSPs) by increasing the concentration of exogenously applied adenosine (1–100 µM) in the absence (upper) and presence of 1 µM of propofol (lower). (B) Concentration-response relationship for adenosine on fEPSP amplitudes in the absence and presence of 1 µM of propofol. Propofol enhanced the inhibitory effects of 1 µM and 10 µM of adenosine on fEPSP amplitude (n = 7; *P < 0.05 compared with adenosine alone, unpaired t-test).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We have demonstrated that propofol depressed the PS, fEPSP, and Mg2+-free epileptiform activity in rat hippocampal slices. Furthermore, we have provided new evidence that adenosine neuromodulation is involved in the inhibitory effect of propofol on excitatory synaptic transmission.

Propofol 1 µM, by itself, decreased the fEPSP amplitude to 65%. This result demonstrated that in rat hippocampal slices, propofol depressed glutamatergic excitatory synaptic transmission. Orser et al. (13) have reported that in cultured hippocampal neurons, propofol inhibited the N-methyl-D-aspartic acid subtype of glutamate receptor. In addition, 1 µM of propofol had a profound effect in increasing PPI of PSs evoked in the CA1 area. This result demonstrated that a significant effect on GABAA-mediated recurrent inhibition occurred at a small propofol concentration. When a patch-clamp technique was used with cultured murine hippocampal neurons, 2 µM of propofol increased the frequency of GABA-activated conductance events (14). Furthermore, propofol (0.1 µM and 1 µM) enhanced the response to GABA in dissociated hippocampal pyramidal neurons (9).

In the present study, adenosine depressed the fEPSP amplitude in a dose-dependent manner. Adenosine is an endogenous neuromodulator that is capable of inhibiting synaptic transmission, particularly in the hippocampus (15). With respect to the action of IV anesthetics on adenosine receptor function, pentobarbital inhibited adenosine uptake (16) and depressed fEPSP via an adenosine A1 receptor-dependent mechanism (17). The present investigation is the first to examine the effects of propofol on adenosinergic neurotransmission in rat hippocampal slices. The observation that propofol enhanced the inhibitory effect of exogenously applied adenosine on fEPSP amplitude confirms an interaction of the anesthetic with the adenosine system. There are two main adenosine metabolic enzymes: adenosine kinase and adenosine deaminase (15). A propofol-induced inhibition of these enzymes would be a possible mechanism by which propofol could potentiate the inhibition by adenosine. Furthermore, aminophylline and DPCPX antagonized the inhibitory effect of propofol on the fEPSP. However, pretreatment with DMPX did not influence propofol-induced fEPSP depression. These results indicate that adenosine neuromodulation through A1 receptors could be involved in propofol-induced depression of excitatory synaptic transmission.

We demonstrated in rat hippocampal slices that propofol inhibited epileptiform activity. With regard to the effects of propofol on experimentally induced seizures in vitro, Rasmussen et al. (18) demonstrated (in rat hippocampal slices) that propofol inhibited spontaneous epileptiform discharges in the CA3 region induced by Mg2+-free ACSF. It has not been reported that propofol can produce an activation of epileptiform discharges in vitro. However, several studies have suggested a convulsant role for propofol in vivo. Bansinath et al. (19) reported that a pretreatment with propofol enhanced the convulsive potency of kainic acid, quisqualic acid, and strychnine. In addition, Hasan and Woolley (20) also investigated, in behaving rats using an ISI of 32 ms, the effects of propofol on paired-pulse facilitation. They showed that the PS2 was inhibited during propofol-induced sleep, but an overshoot of the PS2 amplitude was observed during recovery. The results of these in vivo studies may help explain the occurrence of the seizure-like events associated with the clinical use of propofol.

The present investigation sought to clarify the mechanisms of the anticonvulsant action of propofol in a Mg2+-free model of epileptiform activity. We examined the effects of propofol on an in vitro model of epilepsy in the presence of GABAA receptor antagonists. A competitive GABAA receptor antagonist, bicuculline, was unlikely to antagonize the effect of 1 µM of propofol on epileptiform activity. However, a specific chloride channel blocker, picrotoxin, partly antagonized the effect of 1 µM of propofol on epileptiform activity. This suggests that propofol exerts its anticonvulsant action by promoting inhibitory synaptic transmission directly on the chloride channel, not by potentiating GABA at the GABAA receptor. A contribution of the chloride channel to an anticonvulsant action of propofol has also been reported in several other studies. For example, Rasmussen et al. (18) demonstrated that larger concentrations of propofol, compared with other chemoconvulsants, were required to reduce the discharges induced by picrotoxin.

We also examined the effects of propofol in an in vitro model in the presence of adenosine receptor antagonists. A nonselective adenosine receptor antagonist, aminophylline, antagonized the effect of 1 µM of propofol on epileptiform activity. An A1 receptor antagonist, DPCPX, partly antagonized the anticonvulsant action of propofol, whereas an A2 receptor antagonist, DMPX, failed to affect the effect of 1 µM of propofol on epileptiform activity. These results suggest that adenosine neuromodulation through the A1 receptor is involved in the anticonvulsant action of propofol. It seems unlikely that an A2 receptor-mediated mechanism contributes to the anticonvulsant action of propofol in a Mg2+-free model of epilepsy. Adenosine accumulation reduces adenylate cyclase activity through A1 receptor, thereby reducing transmitter release (15). In hippocampal neurons, activation of the A1 receptor also causes hyperpolarization of the cell membrane with a concomitant decrease in the membrane resistance by an increased potassium conductance (15). Such presynaptic and postsynaptic effects of adenosine are possible reasons for the anticonvulsant action of propofol. The reason why aminophylline significantly, but DPCPX only partly, impaired the anticonvulsant effect of propofol is unknown. One explanation could be that the adenosine A1 receptor might be inaccessible to antagonists. Some reports have noted that tightly bound adenosine prevents the binding of DPCPX (21,22). Another explanation is that aminophylline may act on other sites in addition to the adenosine receptor. Muranaka and Akaike (23) reported that theophylline has the ability to block three different potassium ion channels. In addition, aminophylline is a nonselective phosphodiesterase inhibitor (24). This raises the possibility that aminophylline might offset the anticonvulsant action of propofol.

In summary, the present study has provided evidence that propofol inhibits, in an in vitro model, epileptiform activity in the rat hippocampus. Adenosine neuromodulation through the A1 receptor may contribute to the anticonvulsant action of propofol.


   Acknowledgments
 
The authors thank Professor Hiroshi Iwasaki (Department of Anesthesiology and Critical Care, Asahikawa Medical College) for his guidance and the use of his facilities and Dr. Kaoru Takakusaki (Department of Physiology, Asahikawa Medical College) for his support and comments on the manuscript.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 6, 2004.




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X. Chen, S. Shu, and D. A. Bayliss
Suppression of Ih Contributes to Propofol-Induced Inhibition of Mouse Cortical Pyramidal Neurons
J Neurophysiol, December 1, 2005; 94(6): 3872 - 3883.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press