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Anesthesiology:
Laboratory Investigation

Propofol Reduces Neuronal Transmission Damage and Attenuates the Changes in Calcium, Potassium, and Sodium during Hyperthermic Anoxia in the Rat Hippocampal Slice

Amorim, Pedro MD; Chambers, Geoffrey MS; Cottrell, James MD; Kass, Ira S. PhD

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Abstract

Background: Propofol reduces cerebral blood flow, cerebral metabolic rate for oxygen, and intracranial pressure and is being increasingly used in neuroanesthesia. In vivo studies have yielded conflicting results on its ability to protect against ischemic brain damage. In the current study, an in vitro model was used to examine the mechanism of propofol's action on anoxic neuronal transmission damage.
Methods: A presynaptic pathway was stimulated in the rat hippocampal slice to elicit a postsynaptic population spike in the CA1 region. The effects of propofol (20 micro gram/ml), its solvent intralipid or no drug, on the population spike before, during, and 60 min after anoxia at 37 degrees Celsius or 39 degrees Celsius were examined. Intracellular adenosine triphosphate (ATP), Sodium, and Potassium were measured in dissected CA1 regions at 37 degrees Celsius and 39 degrees Celsius after 5 min of anoxia;45 Calcium influx was measured after 10 min of anoxia.
Results: Propofol did not improve recovery after 5, 6, or 7 min of anoxia at 37 degrees Celsius. Recovery of the population spike after 6 min of anoxia at 37 degrees Celsius was 62 plus/minus 11% with propofol, 35 plus/minus 15% with intralipid, and 44 plus/minus 10% in untreated tissue (NS). After 5 min of anoxia at 39 degrees Celsius, there was significantly better recovery of the population spike with propofol (76 plus/minus 12%) than with intralipid (11 plus/minus 6%) or no drug (13; plus/minus 5%). Propofol, but not intralipid, reduced the population spike amplitude before anoxia. At 37 degrees Celsius, anoxia caused significant changes in ATP (62% of normoxic concentration), Calcium (115%), Sodium (138%), and Potassium (68%). Both propofol and intralipid significantly attenuated the changes in ATP (78% and 82% of normoxic concentration) and Calcium (104% and 103%). Sodium changes were attenuated by propofol (95%) but not intralipid; Potassium concentration was not affected by either drug. At 39 degrees Celsius, for most parameters, anoxia caused more marked changes: ATP was 23% of normoxic concentration, Calcium 116%, Sodium 185%, and Potassium 48%. Both propofol and intralipid attenuated the decrease in ATP (56% of normoxic); propofol, but not intralipid, significantly attenuated the changes in Calcium (100%), Sodium (141%), and Potassium (63%).
Conclusions: Propofol improved electrophysiologic recovery from anoxia during hyperthermia but not normothermia. At 37 degrees Celsius propofol attenuated the changes in ATP, Sodium, and Calcium, however, this did not result in improved recovery. At 39 degrees Celsius the changes in ATP, Sodium, and Potassium caused by anoxia were greater than at 37 degrees Celsius; this could explain why electrophysiologic damage was worsened. Improved recovery with propofol at 39 degrees Celsius may be explained by its attenuation of the changes in Calcium, Sodium, and Potassium at this temperature. The decrease in ATP was attenuated by both propofol and intralipid and therefore cannot explain the improved recovery. (Key words: Anesthetics, hypnotics: propofol. Brain, hippocampal slice: adenosine triphosphate; anoxia; calcium; ischemia; potassium; sodium. Ions: calcium; potassium; sodium. Electrophysiology: evoked population spike; extracellular recording.)
PROPOFOL is an intravenous anesthetic that is being used increasingly for neuroanesthesia. [1] Propofol reduces cerebral blood flow, [2,3] cerebral metabolic rate for oxygen, [4,5] and intracranial pressure, [6,7] and produces faster recovery than thiopental. [8,9] These properties make propofol desirable for induction and maintenance of anesthesia for central nervous system surgical procedures.
The effects of propofol on cerebral ischemia have been studied in vivo. Propofol improved neurologic outcome and decreased neuronal damage after right common carotid artery occlusion and hypotension (incomplete global ischemia) in rats. [10] However, propofol failed to attenuate neuronal damage in rats subjected to temporary middle cerebral artery occlusion (focal ischemia). [11] Propofol was also of no benefit in decreasing ischemic damage in cats subjected to profound hypotension [12] or in preventing neurologic damage after spinal cord ischemia in dogs. [13] Because the results of these studies are conflicting, we used the rat hippocampal slice to study the effect of propofol on anoxic brain damage.
The electrophysiologic recovery after exposure to anoxia was examined to determine if it was improved by propofol. Because improved neuronal recovery from anoxia has been related to better preservation of adenosine triphosphate (ATP), [14,15] reduction of intracellular calcium accumulation, [16,17] and blockage of sodium and potassium channels, [18] we measured ATP levels, calcium influx, and intracellular sodium and potassium values to investigate the mechanisms of propofol's action.
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Methods and Materials

The experiments were approved by the Institutional Animal Care and Use Committee of the State University of New York‐‐Health Science Center at Brooklyn. The methods used were reported previously. [19,20] Adult (110–120 days old) male Sprague‐Dawley rats were decapitated and the brain rapidly removed and dissected to obtain the hippocampi. Each hippocampus was sliced transversely to its long axis so that several 500‐micro meter thick slices were obtained. The slices were then secured to nylon mesh mounted on a Plexiglas grid. Throughout these steps the tissue was kept cold (4 degrees Celsius). For the electrophysiologic studies, a grid holding several slices was placed in a chamber where the slices were continuously superfused with artificial cerebral spinal fluid (aCSF) at a rate of 60 ml/min. The composition of the aCSF was (in mM): NaCl 126; KCl 3; KH2 PO4 1.4; MgSO4 1.3; CaCl2 1.4; NaHCO3 26; glucose 4; pH 7.4. The aCSF was aerated with 95% Oxygen2 and 5% CO sub 2 and the temperature in the tissue chamber was maintained at 37 degrees Celsius. After incubating the slices for 60 min, a bipolar metal electrode was used to stimulate the Schaffer collateral pathway supramaximally. A single tungsten electrode was placed in the cell body layer of the CA1 region to record a postsynaptic population spike, from the CA1 pyramidal cells. After a stable response was obtained, the parameters and position of the electrodes were maintained and the slice was stimulated every 10 s. The electrophysiologic responses were quantified by measuring the amplitude of the postsynaptic population spike. Signal acquisition and measurements were performed using an AD converter (Data Translation 2801A board, Marlboro, MA, with HEM Snapshot Storage Scope software, Southfield, MI). Measurements were taken as the average of five consecutive readings.
Anoxia was generated by bubbling 95% Nitrogen2 and 5% CO sub 2 through the aCSF in the reservoir. After the anoxic period, normoxic superfusion was resumed and the slices were allowed to recover for 60 min. The ability of the slices to recover from the anoxic insult was evaluated by dividing the amplitude of the first spike of the population spike complex measured 60 min after anoxia, by its preanoxic and predrug amplitudes and expressed as a percentage. Recovery was assessed after 60 min of reoxygenation; prolonging the reoxygenation up to 3 h does not affect recovery (unpublished observations).
Figure 1
Figure 1
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Propofol (20 micro gram/ml) in its clinical formulation (Stuart Pharmaceuticals, Wilmington, DE), was studied at 37 degrees Celsius and 39 degrees Celsius. For the normothermic experiments, propofol was added to the aCSF either 20 min (Figure 1(A)) or 80 min (Figure 1(B)) before anoxia, was present during anoxia, and washed out 10 min after reoxygenation was initiated. For the hyperthermic experiments, 20 min after propofol was added the temperature was increased to 39 degrees Celsius and kept at that level for 60 min before, during, and 10 min after anoxia (Figure 1(C)). In another series of experiments, 20 min after propofol was added the slices were subjected to anoxia and the temperature was allowed to increase to 39 degrees Celsius during the initial 3 min of the anoxic period (Figure 1(D)). In some experiments, propofol was added only after the temperature increase (Figure 1(E)). Intralipid, a fat emulsion that is the solvent for propofol in its clinical formulation, was used as one control. The amount of intralipid present in 20 micro gram/ml of propofol (0.2% v/v) was added to the aCSF as described for propofol. Experiments in which neither propofol nor intralipid was added served as an additional control.
The population spike is a complex that has one presynaptic spike and usually more than one postsynaptic spike. The first postsynaptic spike is the largest and the one that was used to evaluate recovery from anoxia. The number of postsynaptic spikes were counted. The amplitudes of the spikes following the first were measured and added together to obtain a variable that we called "combined amplitude of the second and remainder spikes." To examine the effect of propofol on the population spike complex before anoxia, a "reference value" was measured just before drug addition. The treatment was allowed to progress for 20 min and a second measurement was made. The effect of the treatment was calculated as the second measurement divided by the reference value obtained in that slice, and expressed as a percentage. These results were compared to the measurements obtained in untreated slices. In the experiments performed at 39 degrees Celsius, 20 min after adding the drug (or after the same time in the untreated group), the temperature was increased. After 20 min of exposure to 39 degrees Celsius (40 min after adding the drug) another measurement was made, divided by the reference value obtained in that slice (before drug addition or the change in temperature) and expressed as a percentage. These results were averaged and compared to the measurements made in untreated slices after the same exposure time to 39 degrees Celsius.
For biochemical studies, rat hippocampal slices were obtained as described for the electrophysiology. Four methyl methacrylate polymer grids containing slices obtained from one animal were placed in four beakers containing aCSF. The aCSF was aerated with 95% Oxygen2 and 5% CO2. The beakers were placed in a water bath to control the temperature. Anoxia was generated by abruptly replacing the normoxic gas mixture with 95% Nitrogen2 and 5% CO2. The experimental design of the biochemical experiments matched the one described for the electrophysiology. There were four experimental groups. Three were subjected to anoxia: slices in group one received propofol, in group two intralipid, and in group three no drug. Slices in group four received no drug and remained normoxic.
Adenosine triphosphate was measured in slices incubated as described earlier and subjected to a period of 5 min of anoxia. After anoxia, or an equivalent time period, the slices were rapidly frozen in liquid nitrogen, and subjected to lyophilization. The dry tissue was dissected to obtain the CA1 region extending from the stratum radiatum to the alveus including the CA1 pyramidal cell layer. The dissected CA1 regions were then weighed. Adenosine triphosphate was extracted by homogenizing the tissue in 3N ice‐cold perchloric acid and measured after neutralization using the firefly luciferin‐luciferase assay. [21].
Calcium influx was measured using radioactive tracers. [22] Radioactive calcium (sup 45 Calcium, 0.5 uCi/ml) was added to each group for 10 min at the beginning of each treatment period. Control slices were incubated in45 Calcium for 10 min during normal oxygenation. Because this technique is not sensitive to brief periods of anoxia, 10 min of anoxia was used. At the end of the experiment, the slices were taken from the beakers and immediately placed in agitated ice‐cold modified aCSF containing 2 mM LaCl3 for 20 min. This was done to wash out the extracellular45 Calcium while preserving intracellular45 Calcium. [22] Modified aCSF, which was used to prevent precipitation of the LaCl3, contains (in mM): NaCl 158; KCl 4; MgSO4 1.3; LaCl sub 3 2. The slices were then taken from the La wash, blotted, frozen in liquid nitrogen, and subjected to lyophilization. The CA1 regions were dissected, weighed, dissolved in 70% HNO3, diluted with water, and counted in a liquid scintillation counter. [22].
Sodium and potassium concentrations were measured in the dissected CA1 region after 5 min of anoxia. The slices were treated as described earlier until the end of the experimental period, when they were removed from the beakers and submerged in ice‐cold isotonic sucrose for 10 min to wash ions from the extracellular space. Sodium washout time had been previously evaluated by measuring the amount of sodium left in the tissue after different washout periods. [18] Ten minutes in sucrose solution allowed the washout of extracellular sodium with only minimal effect on intracellular levels. The slices were then dissected and the CA1 regions obtained from slices on the same methyl methacrylate polymer grid (5 slices per grid) were pooled and placed in preweighed tubes, dried at 90 degrees Celsius for 18 h, and weighed. After dilute nitric acid (0.1 N) was added, the tissue was shaken for 18 h and the supernatant, after centrifugation, was assayed using a flame photometer.
All values are expressed as the mean plus/minus SEM. Statistical analysis was performed using analysis of variance and a two‐tailed unpaired Student's t test; if the standard deviations of the groups being tested were significantly different (F‐test), the Welch test was used. When appropriate, nonparametric tests were used (specific tests are indicated in results). Instat2 from GraphPad Software, Inc. (San Diego, CA) was used for statistical analysis.
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Results

Population Spike Recovery after Anoxia
Table 1
Table 1
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The first experiments were performed at 37 degrees Celsius (Figure 1(A and B) for time lines of experimental protocol). The population spike recovered to 66 plus/minus 9% of its preanoxia level in untreated slices after 5 min of anoxia; in propofol‐treated slices it recovered to 71 plus/minus 6% (NS). When the anoxic period was increased to 6 min, the population spike recovered to 44 plus/minus 10% in untreated slices; recovery with propofol (20 micro gram/ml) was 62 plus/minus 11%, and with intralipid (the solvent of the clinical formulation of propofol) 35 plus/minus 15%. Neither drug was significantly different from the untreated slices. A larger concentration of propofol (40 micro gram/ml), did not significantly improve recovery of the population spike (36 plus/minus 20%) compared to untreated slices (Table 1). With 7 min of anoxia, untreated slices recovered to 10 plus/minus 5%; the recovery of propofol‐treated slices (19 plus/minus 6%) was not significantly different (Table 1). A longer exposure to propofol (80 min) before 7 min of anoxia, did not significantly improve recovery (27 plus/minus 9%) when compared to untreated slices (24 plus/minus 9%; Table 1).
Figure 2
Figure 2
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In a second series of experiments, the temperature was increased to 39 degrees Celsius for 60 min before anoxia beginning 20 min after the drug was added (or after the same period in untreated slices). The temperature was kept at 39 degrees Celsius throughout the anoxic period and during the initial 10 min of reoxygenation (Figure 1(C)). Untreated slices subjected to 5 min of anoxia exhibited poor recovery (13 plus/minus 5%) (Table 1). Recovery of the population spike improved significantly (76 plus/minus 12%) when propofol was present. Intralipid did not improve recovery (11 plus/minus 6%). Figure 2 shows raw data from two individual experiments performed at 39 degrees Celsius, illustrating the disappearance of the population spike during anoxia and the improved recovery seen in propofol treated slices during reoxygenation.
In a third series of experiments, propofol was added 20 min before anoxia, but the temperature increased to 39 degrees Celsius only during the initial 3 min of the anoxic period (Figure 1(D)). Untreated slices showed 9 plus/minus 3% recovery of the population spike after 5 min of anoxia (Table 1). Propofol significantly improved recovery of the population spike (75 plus/minus 14%). The recovery with intralipid was not different from untreated slices (9 plus/minus 6%).
In a fourth series of experiments, propofol was added to the preparation 30 min after the increase in temperature to 39 degrees Celsius (Figure 1(E)). Recovery in propofol treated slices after 5 min of anoxia was 19 plus/minus 6%, not statistically different from untreated controls (Table 1).
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Postsynaptic Population Spike before Anoxia
Figure 3
Figure 3
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The effect of propofol on the population spike complex before anoxia was examined. At 37 degrees Celsius, the amplitude of the first spike of the population spike complex in propofol‐treated slices was 82 plus/minus 4% of its predrug amplitude obtained 20 min previously; in untreated slices it was 101 plus/minus 1% of its value obtained 20 min before. This was a statistically significant difference (Figure 3). At 39 degrees Celsius, the amplitude of the first spike in propofol‐treated slices was 77 plus/minus 6% of its predrug value obtained 40 min previously; in untreated slices it was 98 plus/minus 3% of its value measured 40 min before. This difference was significant (Figure 2 and Figure 3). Intralipid had no effect on the amplitude of the first spike at either 37 degrees Celsius (102 plus/minus 4%) or 39 degrees Celsius (102 plus/minus 9%; Figure 3).
The combined amplitudes of the second and remainder postsynaptic spikes in propofol‐treated slices at 37 degrees Celsius were 21 plus/minus 3% of their predrug value; in untreated slices at 37 degrees Celsius they were 104 plus/minus 2% of their value obtained 20 min before (P < 0.05; Figure 3). At 39 degrees Celsius, the combined amplitudes of the second and remainder spikes in propofol‐treated slices were 28 plus/minus 6% of their predrug value; in untreated slices they were 116 plus/minus 8% of the value obtained 40 min before (P < 0.05; Figure 2 and Figure 3). Intralipid did not cause significant changes in the combined amplitude at either 37 degrees Celsius (119 plus/minus 11%) or 39 degrees Celsius (147 plus/minus 26%; Figure 3).
The latency of the first postsynaptic spike in untreated tissue at 37 degrees Celsius was unchanged after 20 min (99 plus/minus 1% of its latency 20 min before); after 20 min of propofol, the latency was slightly, but significantly, prolonged (106 plus/minus 1% of its latency before the addition of propofol; Figure 3). At 39 degrees Celsius, the latency of the first postsynaptic spike in untreated tissue was 97 plus/minus 2% of its latency 40 min before; propofol did not change the latency significantly (100 plus/minus 1%; Figure 3). Intralipid did not change the latency at either temperature (Figure 3).
Table 2
Table 2
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The number of postsynaptic spikes were counted and statistical comparisons between the treated and untreated groups were made using a nonparametric test (Mann‐Whitney). At 37 degrees Celsius, the average number of spikes was 3.8 plus/minus 0.3 in untreated slices, and 2.1 plus/minus 0.2 in propofol‐treated slices (P < 0.05; Table 2). In intralipid‐treated slices, the number of spikes increased significantly (Table 2). At 39 degrees Celsius, the average number of spikes in propofol treated slices was 2.3 plus/minus 0.2; in untreated slices it was 4.3 plus/minus 0.3 (P < 0.05). In intralipid‐treated slices, the number of spikes was significantly greater than in the untreated slices (Table 2).
Figure 4
Figure 4
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A separate series of experiments evaluated whether the effect of propofol on the population spike could be completely reversed after drug washout. Slices incubated at 37 degrees Celsius and not subjected to anoxia, showed significant reduction in the amplitude of the population spike by propofol (68% with 35 min of exposure); after propofol was washed out, the population spike recovered to 98% of its original amplitude (Figure 4).
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Postsynaptic Population Spike during Anoxia
Table 3
Table 3
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The time from onset of anoxia to the definitive loss of the population spike complex in untreated slices, was 194 s at 37 degrees Celsius and 177 s at 39 degrees Celsius (NS; Table 3). In slices treated with propofol at 37 degrees Celsius, the time until loss of the signal during anoxia was reduced, however, this time was not affected at 39 degrees (Table 3). Intralipid prolonged the time to the loss of the signal at 37 degrees Celsius but did not change it at 39 degrees Celsius (Table 3).
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Biochemical Studies at 37 degrees Celsius
Table 4
Table 4
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The ATP concentration in untreated slices at 37 degrees Celsius subjected to 5 min of anoxia decreased significantly to 62% of the concentration in slices not subjected to anoxia (Table 4). Propofol significantly attenuated the reduction in ATP to 78% of the normoxic concentration. Intralipid also significantly attenuated the decrease in ATP (82%).
Calcium uptake increased significantly to 115% when slices were subjected to 10 min of anoxia (Table 4). When the tissue was treated with propofol, the increase in Calcium uptake that occurred with anoxia was significantly attenuated (104%). Intralipid also significantly attenuated the increase in Calcium uptake (103%).
The intracellular sodium concentration increased significantly during 5 min of anoxia to 138% of that measured in slices not subjected to anoxia (Table 4). Propofol significantly attenuated that increase: the sodium concentration after 5 min of anoxia with propofol was 95% of the normoxic concentration. Intralipid (120%) did not significantly attenuate the increase in sodium (Table 4).
The intracellular potassium concentration in untreated anoxic slices was significantly reduced to 68% of that measured in slices not subjected to anoxia (Table 4). In propofol‐treated slices subjected to 5 min of anoxia, the potassium concentration decreased to 79% of the normoxic concentration. In slices treated with intralipid, potassium decreased to 84%. Neither propofol nor intralipid significantly attenuated the decrease in potassium seen with anoxia.
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Biochemical Studies at 39 degrees Celsius
Table 5
Table 5
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The ATP concentration in anoxic slices at 39 degrees Celsius decreased significantly to 23% of that measured in slices not subjected to anoxia (Table 5). When the tissue was treated with propofol, the reduction in ATP observed during anoxia was significantly attenuated; intralipid also attenuated the reduction. The ATP concentration decreased to 56% of the normoxic concentration with either propofol or intralipid.
Calcium uptake during 10 min of anoxia increased significantly to 116% of normoxic slices (Table 5). When the tissue was treated with propofol, the increase in Calcium uptake that occurred with anoxia was prevented (100%). In slices treated with intralipid, Calcium uptake during anoxia reached a level (114%) similar to that in untreated, anoxic tissue.
The intracellular sodium concentration measured in slices subjected to 5 min of anoxia increased significantly to 185% of the normoxic concentration (Table 5). Propofol caused a significant attenuation of the increase in sodium observed with untreated anoxia (141% vs. 185%). Intralipid did not significantly attenuate the increase in sodium (Table 5).
The potassium concentration during 5 min of anoxia was significantly reduced to 47% of that measured in untreated slices not subjected to anoxia (Table 5). Propofol significantly attenuated the decrease in potassium seen with anoxia; the potassium concentration decreased to 63%. Intralipid did not significantly attenuate the reduction of potassium.
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Discussion

Our results demonstrate that propofol does not improve recovery from anoxia at 37 degrees Celsius. Although there was a trend toward better recovery in propofol‐treated slices, it was never statistically significant. Changing the duration of anoxia, increasing the dose or extending the duration of exposure to propofol, did not improve recovery significantly. When the temperature was increased to 39 degrees Celsius before and during anoxia, propofol reduced electrophysiologic damage significantly. This effect occurred only if propofol was present before the increase in temperature; hyperthermia once present, may trigger events that are not reversed by propofol. Intralipid did not improve recovery under any circumstances, demonstrating that this effect of propofol is not due to its solvent.
Our results suggest that a brief increase in temperature during anoxia causes as much damage as a prolonged exposure to the same temperature before and during anoxia. With the increase in temperature from 37 degrees to 39 degrees before anoxia, the average number of spikes increased (P = 0.016, Wilcoxon test; Table 2). This may have resulted from hyperthermia‐induced excitability, possibly caused by an increase in glutamate release. [23,24] Recovery in untreated slices was markedly reduced when the temperature increased (Table 1). Our results demonstrate that moderate hyperthermia increases anoxic neuronal damage; this has also been shown in vivo. [25,26].
The effects of propofol on electrophysiologic activity were reversed after the drug was eliminated. Therefore, propofol did not impede our ability to measure the recovery of the population spike after anoxia. Although propofol reduced electrical activity in the slices both at 37 degrees Celsius and 39 degrees Celsius, this effect may have been more beneficial at the higher temperature because at 39 degrees Celsius the number of spikes was increased.
There is recent evidence that propofol activates gamma‐aminobutyric acid (GABAA) receptors in isolated rat hippocampal neurons. [27] This inhibitory effect would reduce synaptic transmission and electrical activity and might explain the reduction in electrical activity that was observed. Propofol reduced the second and remainder spikes of the population spike complex more effectively than it reduced the first spike; this may result from an increase in recurrent inhibition. Albertson et al. found an increase in recurrent inhibition with propofol in the dentate region of the hippocampus. [28] The reduced spiking also may have been due to a direct reduction of glutamate release or blockade of the glutamate receptor. [29].
During anoxia, oxidative phosphorylation is halted and ATP production is dramatically reduced. Because energy use exceeds its supply, ATP concentrations decrease rapidly, the neurons become unexcitable and irreversibly damaged. [30] The decrease in ATP during anoxia has been correlated with a lack of recovery of the evoked responses after anoxia. [31,32] In our experiments, ATP concentrations were reduced during anoxia at 37 degrees Celsius and further reduced during anoxia at 39 degrees Celsius. Propofol significantly attenuated the decrease in ATP at both temperatures, as did intralipid. The attenuation of the decrease in ATP could be explained by a decrease in energy use as a result of a reduction in electrical activity. Because both propofol and intralipid attenuated the decrease in ATP to a similar extent, the reduction of electrical activity, which was seen only with propofol, is not a likely explanation for the maintained ATP concentrations. Intralipid is an emulsion containing lipids that can be used as an energy source. [33] Because intralipid was present in both groups, this might explain ATP preservation. In spite of the attenuation in the decrease of ATP, electrophysiologic recovery was not improved at 37 degrees Celsius. Because intralipid, which did not reduce damage, also attenuated the decrease in ATP, propofol's effect on ATP is insufficient to explain the reduction in neuronal damage after hyperthermic anoxia.
It has been common to relate the changes in anoxic and ischemic damage caused by temperature with brain energy metabolism; however, studies examining hypothermia and brain protection have argued convincingly that the reduction in metabolism achieved by a small decrease in temperature is not sufficient to explain protection. [34] Our results can be interpreted in a similar way and suggest that hyperthermia triggers cellular events that go beyond the balance between energy supply and demand.
Increased intracellular calcium concentrations are thought to have a major role in neuronal damage associated with anoxia. [29] It has been demonstrated that propofol can block calcium entry into cells: this was shown in ventricular myocytes, [35] synaptosomes, [36] isolated aortic rings, [37] and astrocytes. [1],* We found that45 Calcium uptake during anoxia was attenuated by propofol. At 39 degrees Celsius, propofol, but not intralipid, prevented45 Calcium uptake from increasing during anoxia. This may explain why propofol reduced neuronal anoxic damage at 39 degrees Celsius. Propofol may block the voltage‐gated calcium channels or the n‐methyl‐d‐aspartate (NMDA) receptor ion channels, which also conduct calcium. [38] Our conclusions about calcium are based on the assumption that propofol's effect on calcium influx during 10 min of anoxia are qualitatively similar to its effects during 5 min of anoxia, which could not be measured by our techniques.
Sodium influx has been increasingly implicated in neuronal anoxic and ischemic damage. [15,39,40] The pharmacologic blockade of sodium channels has been associated with reduced neuronal damage. [15,18,41] We found that the increase in sodium that occurs with anoxia at 37 degrees Celsius and 39 degrees Celsius was significantly attenuated by propofol, but not intralipid. The reduced sodium concentration cannot be explained by the effect of propofol on ATP, because intralipid also attenuated the decrease in ATP but did not attenuate the increase in sodium. Thus, a direct action of propofol on sodium entry is likely. Propofol caused a reduction in the number and amplitude of the postsynaptic spikes suggesting that it interferes with transmission. Previous studies have demonstrated that sodium channel blockers like tetrodoxin and lidocaine reduce anoxic sodium levels and improve electrophysiologic recovery [15,41]; propofol may be acting similarly.
Potassium plays an important role in the cascade of events triggered by anoxia. During anoxia there is an increase in the extracellular potassium concentration [30,42] that may be caused by a decrease in potassium uptake by neurons and glial cells and an increased efflux from neurons. High extracellular potassium concentrations may lead to the neuronal depolarization that occurs with anoxia. [20,29,30,43,44] Propofol attenuated the reduction in potassium during anoxia; this would attenuate the rise in extracellular potassium and reduce or delay anoxic depolarization. In myocardial cells, propofol blocks potassium current through the delayed rectifier channel [45]; such an effect may also be present in neurons. The attenuation of the reduction in potassium during anoxia was observed with propofol but not with intralipid and only at 39 degrees Celsius. Thus, this may explain propofol's ability to reduce damage caused by hyperthermic anoxia.
At 37 degrees Celsius, propofol attenuated the changes in ATP, calcium, and sodium during anoxia. This would have been expected to lead to improved recovery. However, propofol did not improve recovery at normothermia. The explanation for this may be that hyperthermic anoxia is not just quantitatively but qualitatively different from normothermic anoxia. There may be cellular events triggered by hyperthermia that occur before anoxia and that determine outcome. Our results show a decrease in ATP and an increase in calcium influx in normoxic slices after the temperature increase, as well as an increase in the number of postsynaptic spikes. Hyperthermia may have a direct effect on cell membranes causing ion channels to open. That propofol reduces damage only if it is present before the temperature increase suggests that there may be phenomena occurring before anoxia that determine the outcome. It may also be that reduced damage at 39 degrees Celsius results from actions other than the ones we examined.
The rat hippocampal slice has been successfully used to examine normal physiologic and pathophysiologic mechanisms. The slices preserve functional interactions and anatomic connections between different neuronal types in the hippocampus. The hippocampal slice also contains the CA1 pyramidal cells that are extremely sensitive to anoxic and ischemic damage. [46] The results obtained in this model have correlated well with in vivo ischemic studies. [18,41].
In our studies we commonly observe multiple spiking; this differs from epileptiform activity in the slice, because: (1) the amplitude of each spike is always smaller than the previous one; (2) there are no wide spikes; and (3) variation between consecutive complexes is minimal. These multiple spikes may occur because unlike some investigators, we use lower concentrations of Ca and Mg, which are closer to those in the extracellular fluid of the brain. Multiple spiking is not unusual in CA1 pyramidal cells in vivo, indeed, these cells have been referred to as complex spike cells. [47].
The hippocampal slice has been used to study the mechanisms of epileptic activity [48]; our results may help clarify the relationship between propofol and seizures. [49] Propofol reduced the number of spikes and the combined amplitudes of second and remainder spikes during normothermia and hyperthermia. This may help explain the mechanism of the antiepileptic properties of propofol seen by others. [50–52].
Propofol did not reduce neuronal damage at normothermia. The propofol concentration that was used (100 micro Meter), correlates with concentrations compatible with burst suppression, [12,53,54] and is a concentration that can be used clinically. When this concentration was doubled we still found no damage reduction under normothermic conditions. Propofol was protective in one recent study that used an in vivo rat model of incomplete global cerebral ischemia. However, in this study, brain temperature, which may differ from rectal temperature, [2],**,*** was not monitored in the animals included in the outcome studies. [10] Moreover, the control group received nitrous oxide, which has additional effects that complicate the interpretation of these experiments. [55–57] Another recent study used a focal ischemia model and did not find protection with propofol. [11] In this study, the brain temperature was maintained precisely at 37 degrees Celsius; the control group received halothane. Although barbiturate protection was previously demonstrated in the same model, [58] propofol is again being compared to another anesthetic complicating the interpretation. Our study eliminated the use of anesthesia in the control group and demonstrated that propofol's effect on anoxic damage is temperature‐dependent. This suggests that temperature and the characteristics of the control group may have been key factors in explaining the contradictory results in vivo. We have previously demonstrated improved recovery with thiopental [18] in our preparation; the current results suggest that at normothermia, at least in vitro, propofol does not offer advantages over barbiturates during ischemia or anoxia.
In conclusion, we have shown that propofol reduces damage during hyperthermic anoxia. This effect appears to be due to an attenuation in calcium and sodium influx and potassium efflux during anoxia. The preservation of ATP may have contributed to propofol's effect but cannot explain it, because it occurred both with propofol and intralipid. Propofol attenuated the changes in Calcium, Sodium, and ATP at 37 degrees Celsius, however, it did not improve recovery. Thus, propofol appears to have cellular effects that are beneficial during an anoxic insult, but it does not seem effective in reducing damage unless the tissue is stressed with hyperthermia. Propofol reduced the electrical activity in the slices, which may have contributed to limit damage.
The authors thank Rodney Rosenberg, who performed preliminary research not reported here, and Eduarda Amadeu, for reading this manuscript.
*Biddle NL, Gelb AW, Kalogeros G, Philp RB, Hamilton JT: Effect of propofol on intracellular concentrations in SK‐N‐SH neuroblastoma cells: Proceedings of the twelfth international congress of pharmacology (abstract P13.6.005), 1994.
**Minamisawa H, Nordstrom C‐H, Smith M‐L, Siesjo BK: The influence of mild body and brain hypothermia on ischemic brain damage (abstract). Stroke 21:1386, 1990.
***Mollenberg O, Hoffman WE, Kochs E, Werner C, Schulte am Esch J: Maintenance of brain temperature during experimental cerebral ischemia in rats (abstract). J Neurosurgical Anesthesiology 5:315, 1993.
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