Anesth Analg 2002;94:331-337
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Activation of Neuronal N-Methyl-D-Aspartate Receptor Channels by Lipid Emulsions
Henry U. Weigt, MD*,
Michael Georgieff, MD*,
Cordian Beyer, PhD
, and
Karl J. Föhr, PhD*
*University Clinic of Anesthesiology, Ulm, Germany; and Department of Anatomy and Cell Biology, University of Ulm, Germany
Address correspondence and reprint requests to Karl Föhr, PhD, Universitätsklinikum Ulm, Universitätsklinik für Anästhesie, Steinhövelstraße 9, 89070 Ulm, Germany. Address e-mail to karl.foehr{at}medizin.uni-ulm.de
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Abstract
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Lipid emulsions are widely used as carriers for hypnotics such as propofol, etomidate, and diazepam. It is assumed that the emulsions alone exert no effect on cellular functions nor influence the pharmacokinetics, pharmacodynamics, or anesthetic and analgetic potency of the hypnotics they carry. To elucidate possible interactions between lipid emulsions and cell membranes, in particular membrane-bound proteins, we investigated the effects of commercially available lipid emulsions on the cell membranes of cultured cortical neurons from the mouse by using the whole-cell configuration of the patch-clamp technique. Of nine lipid emulsions tested, three, i.e., Intralipid®, Structolipid®, and, to a much lesser extent, Abbolipid®, activated membrane currents in the neuronal cells in a dilution-dependent manner. The emulsion-induced currents were not affected by picrotoxin or bicuculline but were inhibited by DL-AP5 and ketamine. The voltage dependence of the currents was influenced by the presence of Mg2+ in a way that is typical for currents conducted by N-methyl-D-aspartate receptor channels. We conclude that Intralipid, Structolipid, and Abbolipid activate N-methyl-D-aspartate receptor channels in cortical neurons.
IMPLICATIONS: Lipid emulsions are widely used as carriers for hypnotics such as propofol, etomidate, or diazepam. We tested nine commercially available lipid emulsions and demonstrate that three of them—Intralipid, Structolipid, and Abbolipid—activate NMDA receptor channels in the membranes of cortical neuronal cells.
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Introduction
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Commercially available lipid emulsions are oil-in-water formulations containing a mixture of oils and egg phosphatides as emulsifiers and glycerol for the adjustment of tonicity. In clinical practice, they are widely used as drug carriers. In addition to numerous formulations designed for experimental use (e.g., for cytostatics), several emulsions contain hypnotics (such as propofol, etomidate, or diazepam) that would otherwise present considerable delivery problems. The administration of drugs in lipid emulsions has been shown to reduce adverse effects usually encountered with nonaqueous solvents, e.g., injection pain. When using these emulsions, however, one must keep in mind that changes in their formulation may influence the pharmacokinetics, pharmacodynamics, or safety characteristics of the carried drug, as demonstrated for propofol (1,2). The characterization of the physicochemical variables of the emulsions, such as particle size, size uniformity, and content of the free drug, has been the subject of numerous recent studies (3). However, knowledge about direct effects of lipid emulsions on membrane receptor channels is still missing.
IV application of medium-chain triglyceride emulsions was reported to have significant dose-related metabolic and neurologic effects in the central nervous system of dogs, accompanied by electroencephalographic changes when plasma octanoate concentrations were in the range 0.5 to 0.9 mM (4). On the cellular level, binding of arachidonic acid (5 µM) and other fatty acids to the N-methyl-D-aspartate (NMDA) receptor has been demonstrated to modulate the channel activity (5,6). Furthermore, various lipid mediators may affect NMDA receptor activity and may play a role in synaptic transmission (7). The NMDA receptor channel plays a special role within the transmitter-gated ion channel family, mainly because of its high permeability to Ca2+ (8). This excitatory amino acid receptor controls several important physiologic processes that are initiated by changes in the intracellular Ca2+ concentration, including long-term potentiation and depression. Overactivation of NMDA receptors may be involved in pathological processes such as ischemic insult or epileptic disorders (9).
The aim of this study was to investigate possible interactions between lipid emulsions and cell membranes, in particular with the NMDA receptor channel. To this end, we cultivated neurons from the mouse cortex and applied various commercially available lipid emulsions to these cells while measuring the membrane conductance.
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Methods
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After approval by the institutional animal care and use committee, adult BALB/c mice were kept in a 12-h dark/light cycle and fed a standard pellet diet. Animals were allowed to mate during a 12-h period, and the day after mating was defined as Day 0 of pregnancy. Pregnant mice on Embryonic Day 15 were anesthetized with 25% chloral hydrate (1 mL/100 g body weight) and killed by decapitation.
The cerebral cortex of the fetal brains was dissected after removal of the striatal and hippocampal tissue. Neuronal cell cultures were initiated as described (10). Briefly, the cortical tissues were dissociated both enzymatically (0.1% trypsin) and mechanically. Cells were plated at a density of 1.8 x 105 cells/cm2 on poly-DL-ornithine-coated (0.5 mg/mL) plastic culture dishes (10 cm2). Cultures were raised with minimum essential medium (Biochrom, Berlin, Germany) supplemented with 5% fetal calf serum and grown for at least 2 wk. The medium was exchanged every second day. Neurons were used for experimentation after 10 to 14 days of cultivation.
For experimentation, cells were first rinsed twice with extracellular solution and thereafter placed in a Petri dish containing a medium that was continuously exchanged at a rate of 4.5 mL/min. The medium contained 140 mM NaCl, 2.7 mM KCl, 1.5 mM CaCl2, 10 mM glucose, 2.5 µM glycine, 100 µM strychnine, and 12 mM HEPES, pH 7.3. Strychnine was excluded when 
-aminobutyric acid (GABA) receptors were investigated. The membrane conductance of the cells was determined at room temperature (23°C–25°C) by using the whole-cell recording variant of the patch-clamp technique (11). The equipment consisted of an EPC-9 amplifier and TIDA software (Heka, Lambrecht, Germany). The patch pipettes were drawn from borosilicate glass, with a pipette resistance of 3–6 M
, when filled with 140 mM CsCl2, 2 mM MgCl2, 2 mM ATP x 2Na, 2 mM EGTA, and 10 mM HEPES, pH 7.2. To improve sealing, the electrodes were briefly dipped into dimethyldichlorosilane 2% dissolved in methylene chloride (12). Membrane currents were recorded either with the membrane potential clamped to -80 mV (to detect changes in the resting membrane conductance) or during a series of stepwise variations of the membrane potential (to obtain current/voltage relationships).
Agents were applied to the cells by using the L/M-SPS-8 superfusion system (List, Darmstadt, Germany). To restrict the presence of the agent to a small volume within the dish, a combination of two perfusion systems was installed, i.e., 1) a global bath perfusion with the inflow set at 4.5 mL/min and an outflow that removed any excess fluid and 2) a local bath perfusion that generated a continuous fluid stream containing the agent in the desired concentration. The local inlet (tip of an eight-barreled pipette) was positioned at a distance of 50–100 µm upstream and the local outlet at approximately 300 µm downstream of the measuring field. A combination of a gravity and a pressure system (MPCU-3 multipressure control unit; Lorenz, Lindau, Germany), adjusted onto eight supply vessels, was used. When lipid emulsions were to be administered, infusion pumps were used and set at a rate of 1 mL/min. The selection among the eight supply vessels connected to the eight-barreled pipette was controlled with magnetic valves.
The commercially available lipid emulsions tested are summarized in Table 1. Intralipid® 10% and 20%, ClinOleic® 20%, and Salvilipid® 20% were purchased from Baxter (Unterschleißheim, Germany); Lipofundin MCT® 20% and Lipofundin N® 20% from Braun-Melsungen (Melsungen, Germany); Abbolipid® 20% from Abbott (Wiesbaden, Germany); and Lipovenös MCT® 20%, Omegaven® 10%, and Structolipid® 20% from Fresenius-Kabi (Bad Homburg, Germany). DL-AP5 acid/DL-2-amino-5-phosphonovaleric acid was purchased by Biotrend GmbH (Köln, Germany). All other drugs were purchased from Sigma (Deisenhofen, Germany).
Statistical analysis was performed with paired Student’s t-tests when comparing the mean results from the same lipid emulsion sample and with unpaired Student’s t-tests when comparing different samples. A difference between results was considered significant when P < 0.05. Results are presented as mean ± SD.
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Results
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Our first aim was to investigate the effect of various lipid emulsions, applied at various dilutions, on the membrane conductance of resting mouse cortical neurons. Because Intralipid is the most commonly used lipid emulsion worldwide, we decided to study this emulsion first and then to relate the effects found with other emulsions to the normalized results obtained with Intralipid. Emulsions were applied for 5 or 10 s, and the membrane current was recorded while the membrane potential was clamped to -80 mV. This short application time was chosen to get identical signal response amplitudes during consecutive applications. Longer application times required much longer recovery intervals after drug application. Typical traces of Intralipid-activated membrane currents are illustrated in Figure 1A. Downward deflection indicates that positive charge (most likely Na+) is carried from the extracellular space into the cell. The observed inward current was not caused by an outflow of anions, because Intralipid-activated inward membrane currents did not change in size and shape when chloride was replaced by the impermeant anion methanesulfonate in the pipette solution (n = 5, data not shown).
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Figure 1. Concentration-dependent activation of membrane currents by lipid emulsions. A, Currents induced by Intralipid 20% (diluted from 1:80 to 1:5) in a representative cell kept at a holding potential of -80 mV. B, Means ± SD of the amplitudes of the currents induced by Abbolipid, Structolipid, and Intralipid (conditions as in A). Dilutions of emulsions are given below each set of columns. Current amplitudes were normalized to the amplitude of the current induced by Intralipid 20% at dilution 1:5. Each column represents an average of 6 to 16 cells. *Significantly different from control; #significantly different from the effect of Abbolipid in corresponding dilutions; +significantly different from the effect of Structolipid in the corresponding dilution.
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The larger the concentration used (i.e., the smaller the dilution), the larger the current. At small Intralipid concentrations, the current was of almost constant amplitude during the entire time of application. Larger concentrations produced a current with a fast initial peak and a slow decay phase. The current did not fully plateau during the short time of application. The effects of Intralipid on the membrane conductance were completely reversible by a brief washout of the emulsion (n = 54 cells). Repeated application of the same dilution resulted in almost identical signal amplitudes (maximum deviation from mean value <10%, not shown). The shape of the conductance change, and also the fact that it was reversible upon washing, led us to postulate that it might be caused by an interaction of the emulsion with ion channels rather than to a nonspecific membrane effect.
Structolipid and Abbolipid also induced concentration-dependent increases in the membrane conductance (Fig. 1B). At the same dilution (1:5), the change in conductance evoked by Structolipid and Abbolipid was approximately 120% and 10%, respectively, of the change evoked by Intralipid. The change observed with Abbolipid was so small that it was only with the smallest dilution (1:5) that the induced membrane currents differed significantly from zero (Fig. 1B and Table 1). The other clinically relevant lipid emulsions tested at dilutions as small as 1:5 (Lipofundin N 20%, Lipofundin MCT 20%, ClinOleic 20%, Omegaven-Fresenius 10%, Salvilipid 20%, and Lipovenös 20%) did not induce detectable membrane currents (Table 1).
Suspecting that ion channels were involved in the increased conductance induced by each of the three emulsions, we looked for the size of the conductance changes in the presence of various ion channel blockers. With both GABA antagonists tested—picrotoxin (100 µM) and bicuculline (100 µM, data not shown)—the amplitude of the Intralipid-induced membrane current was unaffected (n = 6 cells each, no significant effect on peak and plateau membrane currents; Fig. 2A). Picrotoxin blocks GABA-activated chloride channels, whereas bicuculline antagonizes GABAA receptors by competing with GABA for its binding sites. The Structolipid- or Abbolipid-induced membrane conductance changes were also unaffected by 100 µM picrotoxin or bicuculline (n = 4 cells each, data not shown). These findings suggest that GABAA receptor channels are not involved in the described increase in membrane conductance.
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Figure 2. Effects of DL-AP5 and picrotoxin on Intralipid-and N-methyl-D-aspartate (NMDA)-induced membrane currents. A, Picrotoxin (100 µM) does not affect Intralipid 20% (1:5)-induced membrane currents but inhibits -aminobutyric acid (GABA)-induced currents. B, DL-AP5 (100 µM) suppresses Intralipid 20% (1:5)- and NMDA (25 µM)-induced membrane currents (holding potential -80 mV; n = 6 cells each). The records from A and B were obtained from two representative cells.
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To test for a possible involvement of NMDA receptor channels, we performed similar experiments in combination with DL-AP5, a competitive NMDA receptor antagonist, and ketamine, a noncompetitive NMDA receptor antagonist. DL-AP5 (100 µM) and ketamine (100 µM, data not shown) considerably suppressed the Intralipid-induced membrane current (Fig. 2B). Similar results, as illustrated in Figure 2B, were obtained with five other cells tested. The suppressant effect of DL-AP5 was completely reversible after a 1-min period of washout with a DL-AP5-free application of Intralipid. Likewise, the membrane currents induced by Structolipid 20% and Abbolipid 20% (diluted 1:5) were suppressed by DL-AP5 or ketamine at 100 µM (n = 5 cells each, data not shown).
To further specify the origin of the observed conductance change, we determined current/voltage relationships in the absence and presence of external Mg2+. As illustrated in Figure 3, at hyperpolarizing potentials the Intralipid-induced currents were blocked by Mg2+. This behavior suggests that Intralipid most likely activates the NMDA receptor channels.
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Figure 3. Current-voltage relationship of Intralipid-induced membrane currents recorded in the absence and presence of extracellular Mg2+. Average of results obtained with Intralipid 20% (1:5) from nine cells. Stepwise depolarization (20-mV increments) to +80 mV from a holding potential of -100 mV. Mean current amplitudes (± SD) normalized to the maximum current flowing at +80 mV. Insets show families of original traces recorded in the absence and presence of Mg2+.
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Finally, we attempted to "calibrate" the Intralipid-induced activation of the NMDA receptor channels by comparing it with the responses induced by the proper activator, NMDA, in various concentrations. The current induced by Intralipid 20% in a 1:5 dilution had approximately the same amplitude as that induced by 25 µM NMDA (not shown; the estimated 50% effective concentration for NMDA was 32 µM). Lipid emulsions were diluted in extracellular solution without correcting for a potential dilution of ion concentrations. This may lead to a moderate reduction of Na+, the main charge carrier, and to an underestimation of the actual effect, especially at large lipid concentrations.
To determine whether activation of the NMDA receptor channels is mediated via the lipid or the aqueous phase of the emulsion, we investigated two different formulations of Intralipid (10% and 20%). Using the two different formulations in dilutions that yielded identical amounts of lipid, we found no significant difference in the amplitude of the membrane currents (Fig. 4, representative for n = 19 experiments). This suggests that the activation of the NMDA receptor channel arises from components of the lipid phase.
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Figure 4. Membrane currents induced by Intralipid 10% (dilution 1:5) and Intralipid 20% (dilution 1:10). Membrane currents were recorded from the same cell when Intralipid was applied from two different formulations (10% and 20%). The final lipid concentration (2%) is identical in all recordings.
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Discussion
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In this investigation of nine commercially available lipid emulsions, we found that three of them, i.e., Intralipid 20%, Structolipid 20%, and, to a lesser degree, Abbolipid 20%, activated NMDA receptor channels in the membranes of cortical neuronal cells. This is the first report of an interaction between lipid emulsions and ion channels. An investigation of possible effects of Intralipid at a dilution of approximately 1:50 (recalculated) on ligand-gated GABA receptors yielded neither potentiation nor inhibition, nor was an induction of currents of unknown origin reported (13). Emulsions were also reported not to affect the voltage-gated calcium channels of the heart (14).
The mechanism by which membrane currents were induced seemed to be the same for the three emulsions. The currents were blocked by DL-AP5 (100 µM), a competitive NMDA-receptor antagonist, and ketamine (100 µM), a noncompetitive NMDA-receptor antagonist (15), and—as a typical finding indicating the involvement of NMDA receptors (8)—they could also be blocked by extracellular Mg2+ in a potential-dependent manner. Until now, emulsion-induced membrane currents have gone undetected, because experiments are routinely performed in the presence of extracellular Mg2+. However, picrotoxin and bicuculline, both antagonists of GABAA receptors, did not affect the emulsion-induced currents, suggesting that GABA receptors were not involved. This last finding corroborates the above-mentioned earlier study (13). Furthermore, our data indicate that lipid emulsions do not exert their effects via unspecific membrane disruption, because the effects of the lipid emulsions could be antagonized by ion channel blockers.
The mechanisms by which the NMDA receptor channel can be activated or modulated are complex. The channel is not only activated by glutamate, but also by NMDA, aspartate, homocysteic acid, or quinolinic acid (8,16,17). Lipid mediators, such as lysophosphatidic acid, but not oleic acid, potentiate NMDA receptor activity (7). Moreover, its function is modulated by glycine, histamine, steroids, fatty acids, polyamines, Mg2+, and redox drugs (18). Fatty acids may alter the function of integral membrane proteins (19). Because fatty acids are highly enriched in the lipid emulsions, they might alter the lipid environment in the vicinity of ion channels or even directly interact with ion channel proteins. Indeed, a modulation of NMDA receptor channel activity was demonstrated for arachidonic acid (6). Moreover, the 131-residue domain of the NMDA receptor channel is homologous to known fatty acid-binding proteins so that binding of fatty acids to this domain might modulate the activity of the channel (5). A weak point of this possibility is that it does not explain why currents were induced only by Intralipid, Structolipid, and Abbolipid, but not by the other lipid emulsions.
Two aspects of our results should finally be discussed: the in vitro model and dilution. First, we performed our experiments at room temperature. Although the effects of anesthetics on GABAA-induced activity are temperature dependent (20), no data are available on the temperature dependence of anesthetics on the NMDA receptor channel activity. For these experiments, we used the whole-cell recording method and single neuronal cells as a model system. With this technique, interactions of lipid emulsions and NMDA receptor channels can be examined under controlled conditions. However, effects of the blood-brain barrier on the IV-administered drugs are not considered by this model. We do not know whether the activator of the NMDA receptor described here has access to its molecular targets in neurons, and, if so, whether its action is additionally potentiated by the lipid emulsion. Our main interest focuses on the pharmacologic aspect of the NMDA receptor activation by lipid emulsions. Therefore, our experiments were performed in the absence of Mg2+ ions in the extracellular solution, which does not correspond to the physiologic condition. Thus, in vivo the effects of the lipid emulsions may be different, as seen in this in vitro study. Second, membrane currents were induced by Intralipid and Structolipid at dilutions from 1:80 to 1:5. On the basis of the assumption of an injection of 10 mL of lipid emulsion in 5000 mL of circulating blood, which is realistic under clinical conditions, a lipid emulsion concentration of 1:500 is achieved. However, in addition, the total dilution effect of an injected bolus in the circulatory system is dependent on the cardiac output and the injection speed (21). Therefore, it is very difficult to predict corresponding concentrations at the site of action in the brain in vivo. These in vitro results suggest a dose-related activation of membrane currents by lipid emulsions in neuronal cells; however, the in vivo relevance has to be assessed.
A change in the composition of the carrier fat emulsion does not necessarily affect the hypnotic action of propofol (22). This may be quite different when an anesthetic such as Xenon, incorporated in different lipid emulsions, is administered. Propofol acts mainly on GABAA receptors, whereas the inert gas Xenon is suggested to inhibit NMDA channel receptors (23).
Propofol incorporated in a lipid carrier has been clinically used to treat status epilepticus, but its use remains controversial because of concerns that it produces paroxysmal motor phenomena (24). Propofol pretreatment in a mouse model significantly enhanced the convulsive potency of kainic acid and quisqualic acid (24). This action may be, at least partly, responsible for the motor manifestations reported after propofol administration. However, the lipid carrier used in this study was Intralipid. Our finding that Intralipid itself activates the NMDA receptor channel may be significant in understanding the mechanisms of propofol action in combination with Intralipid.
In the human fetal forebrain, peak expression of NMDA receptors and the brain growth spurt occur during Weeks 20 to 22 of gestation, span much of the third trimester of pregnancy, and overlap into the postnatal period (25). During this period, the developing brain is most vulnerable to the excitotoxic effect of NMDA’s having the potential to trigger apoptotic neurodegeneration (26). Our finding that some lipid emulsions activate NMDA channel activity may have relevance because hypnotics in combination with lipid carriers that activate NMDA currents are often used as anesthetics in pediatric and obstetric medicine.
In summary, these in vitro results provide evidence for activation of membrane currents by commercially available lipid emulsions. From nine lipid emulsions tested, we found that three of them, i.e., Intralipid, Structolipid, and Abbolipid, induce membrane currents in neuronal cells in a dilution-dependent manner. Moreover, our results suggest that these lipid emulsions activate NMDA receptors. Further research will be required to fully ascertain the nature and the intrinsic effects of lipid emulsions on all kinds of cellular processes in the brain.
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Acknowledgments
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Supported by Deutsche Forschungsgemeinschaft (WE 1837/2-1).
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Accepted for publication October 2, 2001.
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Abstract
Introduction
