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© 1999 International Anesthesia Research Society
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Abstract |
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Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known. We conducted the present study to evaluate the effect of isoflurane on injury produced by cortical injection of NMDA in vivo and to compare it with dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were anesthetized with isoflurane. NMDA 50 nmoles (5-µL volume) were stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane groups, the end-tidal concentration of isoflurane was maintained at either electroencephalogram (EEG)-burst suppression (BS) doses (2.2%–2.3%, n = 12) or a 1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before the NMDA injection. In the awake group and the dizocilpine group, anesthesia was discontinued on completion of the NMDA injection, and the animals were allowed to awaken. In the animals in the control group (n = 10), 20 µL of artificial cerebrospinal fluid was injected into the cortex. Injury to the cortex was evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses, isoflurane reduced the injury produced by a cortical NMDA injection compared with the awake state (1.74 ± 0.49 and 0.96 ± 0.46 vs 2.34 ± 0.56 mm3; P = 0.02). Dizocilpine reduced cortical injury (0.56 ± 0.27; P = 0.01) compared with the awake state. Injury in the control group was limited to the trauma produced by cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury was not different from the control group.
Implications: Isoflurane can reduce N-methyl-D-aspartate–mediated cortical injury in vivo in a dose-dependent manner. These data are consistent with the previously demonstrated ability of isoflurane to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.
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Introduction |
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Evidence indicates that volatile anesthetics can reduce the cerebral injury produced by focal ischemia. Halothane, sevoflurane, and isoflurane have been shown to reduce cerebral infarct volumes in rodent models of focal ischemia (1,2). Both isoflurane and halothane reduced neuronal injury in rats subjected to severe incomplete hemispheric ischemia (3). Volatile anesthetic-mediated neuroprotection has been demonstrated even in experimental models in which cerebral temperature has been rigidly controlled for 24 h (4). This neuroprotection is apparent even after a recovery period of 7 days after the ischemic insult (2). These data have fostered general agreement that volatile anesthetics can reduce focal ischemic injury. However, the mechanism by which this reduction in injury is achieved is not known.
Studies have focused attention on the role of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the pathophysiology of ischemic neuronal injury. Excessive stimulation of this receptor by glutamate (excitotoxicity) released during ischemia is thought to result in neuronal death (5,6). Indeed, the administration of NMDA receptor antagonists provides neuroprotection (7). In vitro data indicate that isoflurane can inhibit NMDA receptor responses. In cultured hippocampal cells, isoflurane reduced the frequency of NMDA receptor channel opening in response to NMDA application (8). These data suggest that isoflurane might also be able to reduce toxicity produced by excessive NMDA receptor stimulation. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known.
We conducted the present study to evaluate the dose-dependent effects of isoflurane on neurotoxicity produced by NMDA in rats. Isoflurane’s effects were directly compared with those of dizocilpine, a noncompetitive antagonist of the NMDA receptor.
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Methods |
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The study was approved by our institutional animal care and use committee. All experimental procedures were performed in accordance with the guidelines established in The PHS Guide for the Care and Use of Laboratory Animals.
Wistar-Kyoto rats (275–325 g) were fasted overnight; access to water was provided. The rats were anesthetized with an inspired concentration of 5% isoflurane. After the induction of anesthesia, the rats’ tracheas were intubated, and their lungs were mechanically ventilated with an inspired gas mixture of 30% oxygen, balance nitrogen. Ventilation variables were adjusted to maintain normocapnia (PaCO2 35–40 mm Hg). The inspired concentration of isoflurane was reduced to 2.5%. The tail artery was cannulated with PE-50 tubing, and the mean arterial pressure and heart rate were measured continuously. The right external jugular vein was cannulated with PE-60 tubing. A maintenance infusion of isotonic sodium chloride solution (4 mL · kg-1 · h-1) was initiated via the external jugular vein. A rectal temperature probe was inserted to a depth of 6 cm and the rectal temperature was monitored continuously.
The rat’s head was secured in a stereotaxic frame (David Kopf Instruments, Tujunga, CA). The scalp was reflected and the calvaria were exposed via a midline incision. A needle thermistor was inserted between the left temporalis muscle and the cranium. The pericranial temperature was servo-controlled to 37.0 ± 0.2°C with an overhead heat lamp. Platinum needle electrodes were inserted into the scalp in a biparietal configuration. A 4-mm craniectomy, centered 2.8 mm caudal and 2.8 mm lateral to the bregma, was performed. During the craniectomy, the skull was continuously irrigated with room-temperature saline. Care was taken to avoid injury to the underlying dura. Under stereomicroscopic magnification, the dura was carefully incised with a scalpel blade and reflected. Injury to blood vessels in the immediate vicinity was avoided. The craniectomy site was then bathed in warmed artificial cerebrospinal fluid (155.0 mM Na+, 0.83 mM Mg2+, 2.9 mM K+, 132.76 mM Cl-, 1.1 mM Ca2+, pH 7.4). A 28-gauge plastic injection cannula (Plastic One, Roanoke, VA) was inserted into the parietal cortex (2.8 mm caudal and 2.8 mm lateral to the bregma) by micromanipulator to a depth of 2 mm. The animals were left undisturbed for 30 min. Arterial blood gas tensions and serum glucose and hematocrit concentrations were measured during this equilibration period. All wound sites were infiltrated with 0.25% bupivacaine (total dose 0.5 mg).
After the equilibration period, the animals were randomly allocated to one of five experimental groups: awake, dizocilpine, isoflurane 1 minimum alveolar anesthetic concentration (MAC), isoflurane electroencephalogram (EEG)-burst suppression (BS), and saline control groups. In the isoflurane EEG-BS group, the concentration of isoflurane was adjusted to maintain BS of the EEG (2.2%–2.3% end-tidal). In the remaining four groups, the concentration of isoflurane was reduced to 1 MAC (1.2% end-tidal) (9). The animals were undisturbed for an additional equilibration period of 15 min.
In the awake group, 50 µmoles NMDA (5 µL of 10 mM NMDA in saline solution) was injected by an infusion pump at a rate of 1 µL/min. The cannula was removed, and isoflurane administration was discontinued. On resumption of spontaneous ventilation, the animals were removed from the stereotaxic frame and transferred to a heated incubator through which oxygen was continuously flushed. Within 15 min, spontaneous motor activity was evident. In the two isoflurane groups, 50 µmoles of NMDA was injected as described. Isoflurane anesthesia at either 1 MAC or EEG-BS doses was maintained for 5 h after the injection. The animals were transferred to an incubator for observation for another 2 h. In the dizocilpine group, 10 mg/kg dizocilpine was administered IV 15 min before the NMDA injection. Immediately after the NMDA injection, isoflurane anesthesia was discontinued. In the saline control group, 5 µL of artificial cerebrospinal fluid was injected as described. The animals were allowed to awaken. All animals were observed for 2 h after the resumption of spontaneous ventilation.
Two days after the intracortical NMDA injection, the animals were anesthetized with isoflurane. The animals were killed by transcardiac perfusion with 200 mL of heparinized saline, followed by 200 mL of 4% buffered paraformaldehyde. The animals were decapitated, and the brains were left in situ at 4°C for 24 h, then were prepared for histologic analysis. After dehydration in graded concentrations of ethanol and butanol, the brains were embedded in paraffin. Eight-micron thick coronal sections, at intervals of 250 µm, were prepared and stained with hematoxylin and eosin.
Injury to the brain was evaluated by image analysis using NIH Image 1.60 software (National Institutes of Health, Bethesda, MD). The analysis was performed by two observers who had no prior knowledge of the experimental groups. The cortical lesion volume was determined by integration of the injured area in consecutive sections.
The physiologic variables were evaluated by using analysis of variance (ANOVA). The volume of tissue injury was analyzed by using single-factor ANOVA. When ANOVA identified significant differences, post hoc Scheffé’s tests were used for intergroup comparisons. A P value of <0.05 was considered statistically significant. All data are presented as mean ± SD.
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Results |
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We studied 52 Wistar-Kyoto rats (n = 10 per group except in the isoflurane EEG-BS group, in which n = 12). One animal each in the isoflurane 1.0 MAC, dizocilpine, and saline groups were excluded from analysis because NMDA was injected into structures deeper than the cortex. All experimental animals survived the recovery period. No seizure activity was noted.
Physiologic variables are presented in Table 1. There were no differences in mean arterial pressure, heart rate, PaO2, PaCO2, pH, or serum glucose and hematocrit concentrations among the five groups.
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The cortical NMDA injection produced a lesion that was composed of the central area of infarction. This was characterized by loss of both neurons and the neuropil. Surrounding the infarction was a variable region of selective neuronal necrosis (SNN) in which the neuropil was intact. The boundary between the NMDA-induced lesion and the normal cortex was sharp and easily delineated.
A central area of infarction in the cortex at the site of NMDA injection was evident in all the groups except the saline control group. In this latter group, the lesion was limited to trauma produced by cannula insertion. Isoflurane EEG-BS and dizocilpine significantly reduced infarct volumes (Figure 1). The infarct volumes in these groups were not different from those in the saline group, and they were significantly less than those in the awake and isoflurane 1 MAC groups. The lesion was largest in the awake and isoflurane 1 MAC groups. There was no difference between the awake and 1 MAC isoflurane groups.
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SNN was evident in all groups except the saline group. Isoflurane reduced the volume of cortex in which SNN was evident in a dose-related manner (Figure 2). At EEG-BS doses, the SNN volume was not statistically different from that in the saline control group. As expected, dizocilpine reduced the SNN volume, although it was not different from that in the saline control group.
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The total lesion sizes in the five experimental groups are presented in Figure 3. Isoflurane reduced the cortical lesion volume in a dose-related manner. At EEG-BS doses, the lesion volume was not statistically different from that in the saline control group. Dizocilpine reduced lesion volume, although it was not different from that in the saline control group.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Isoflurane reduced neuronal injury produced by the cortical injection of NMDA, an agonist of the NMDA subtype of glutamate receptor, in a dose-related manner. At a concentration of 1.0 MAC, isoflurane reduced lesion size by approximately 30%. In the EEG-BS group, a further reduction (approximately 70%) in cortical lesion size was observed. The extent of injury in this latter group was similar in magnitude to that in the dizocilpine group, and it was not statistically different from the mechanical injury produced by the insertion of cannula into the cortex.
The mechanism by which isoflurane reduces NMDA toxicity is not known. NMDA can produce neuronal injury primarily by two mechanisms. First, increased intracellular calcium concentration in the postsynaptic neuron, produced by excessive NMDA receptor stimulation, can initiate a biochemical cascade that ultimately leads to neuronal death (10). Second, the injection of NMDA into the brain can evoke presynaptic glutamate release (11). The released glutamate can augment the injury produced by NMDA. It is conceivable that isoflurane might reduce NMDA-mediated toxicity by antagonizing both these effects of NMDA. In support of this premise is evidence that indicates that isoflurane and, indeed, other volatile anesthetics can significantly reduce excitatory transmission by both presynaptic and postsynaptic effects.
Studies have shown that isoflurane can inhibit postsynaptic glutamate receptors. In neocortical slices, isoflurane reduces neuronal depolarizing responses evoked by the application of glutamate and NMDA on dendrites (12). Isoflurane also reduces the frequency of NMDA receptor channel opening and the mean open time of the channel in response to stimulation by NMDA (8). The expected increase in intracellular calcium concentration in response to application of NMDA was reduced by isoflurane in cultured hippocampal cells (13) and in neocortical brain slices (14). Halothane and enflurane also have a similar effect in hippocampal vesicles (15). Activation of the NMDA receptor, as measured by glutamate-stimulated binding of dizocilpine, was substantially reduced by isoflurane, halothane, and enflurane (16,17).
The precise mechanism by which volatile anesthetics inhibit NMDA receptor responses is not known. Martin et al. (16) demonstrated that volatile anesthetics significantly reduced glutamate-stimulated binding of dizocilpine to the NMDA ion channel (an indicator of channel opening) in rat cerebrocortical membranes. In addition, the binding of CGS-19755, a competitive NMDA antagonist that binds to the glutamate recognition site of the NMDA receptor, was also significantly reduced by volatile anesthetics. The authors concluded that these effects of volatile anesthetics due not to a direct effect on either the recognition site or the ion channel, but to the inhibition of the channel activation process. Another possible mechanism, although largely unproven, is that volatile anesthetics might modulate the phosphorylation state of the NMDA receptor. Protein kinase-mediated phosphorylation of the NMDA receptor enhances its response to agonist stimulation (18). However, dephosphorylation of the NMDA receptor by protein phosphatases reduces NMDA receptor responses (19,20). Protein phosphatases are activated by small increases in intracellular calcium concentrations (21), and volatile anesthetics have been shown to increase resting intracellular calcium concentrations in hippocampal slices (22). Thus, activation of protein phosphatases during volatile anesthetic-induced anesthesia might reduce NMDA receptor responses.
Volatile anesthetics can reduce excitatory neurotransmission by reducing the concentration of neurotransmitters in the synaptic cleft. In cortical slices, depolarization-induced Ca2+-dependent release of glutamate was substantially reduced by isoflurane in a dose-dependent manner (23). In cerebrocortical synaptosomes, depolarization-induced calcium influx was attenuated by isoflurane (24,25). This reduction in calcium influx was accompanied by a reduction in glutamate release from the synaptosomes. The ability of volatile anesthetics to reduce glutamate release from presynaptic nerve terminals has been attributed to the blockade of presynaptic Na+ (26) and, possibly, Ca2+ channels (24). In addition, it has been suggested that volatile anesthetics can reduce excitatory transmission by increasing the rate of uptake of excitatory neurotransmitters from the synaptic cleft. High-affinity uptake of glutamate into cerebral synaptosomes is dose-dependently increased by isoflurane (27). Similarly, glutamate uptake by astrocytes has been shown to be increased by isoflurane, halothane, and enflurane (28).
The available data suggest that volatile anesthetics can reduce excitatory transmission by inhibiting the release of neurotransmitters from the presynaptic terminals and by inhibiting the responses of postsynaptic receptors. The ability of isoflurane to reduce NMDA-evoked glutamate release and to inhibit NMDA receptor-mediated responses probably contributed to the reduction in NMDA-mediated cortical injury that we observed.
Our results may also be relevant to a discussion of anesthetic-mediated reduction in ischemic neuronal injury. Both isoflurane and halothane reduce infarct volumes in animals subjected to focal cerebral ischemia. It is generally accepted that the uncontrolled release of glutamate during ischemia and the consequent excessive stimulation of postsynaptic glutamate receptors play a major role in the initiation of neuronal injury (29). The results of the present study are the first demonstration that volatile anesthetics can also reduce excitotoxicity in vivo in doses that also decrease ischemic neuronal injury. Caution in the interpretation of the data must be exercised because the excitotoxicity was produced in healthy brain tissue with adequate blood flow. Whether isoflurane can also reduce NMDA-mediated injury in the setting of ischemia remains to be determined. Nonetheless, our results provide support for the premise that volatile anesthetics reduce ischemic neuronal injury by attenuating excitotoxicity.
Finally, we want to clarify the rationale for the dose of NMDA that was chosen for cortical injection. Intraparenchymal NMDA injection can produce seizure activity that can be sustained for several hours after injection (30). Sustained seizure activity can not only augment direct NMDA toxicity, but can also produce neuronal injury in brain regions remote from the site of injection (30). This can make it difficult to separate the contribution of direct excitotoxicity and seizure activity to the extent of injury. To eliminate the potential effect of seizures, we selected a dose of NMDA that produced a defined cortical lesion, but one that did not evoke seizure activity. As a result, the cortical lesion observed was due entirely to the direct excitotoxic effects of NMDA. This was confirmed by the lack of neuronal death in remote brain locations (e.g., hippocampus), in which injury would be expected to occur with prolonged seizure activity.
In summary, isoflurane reduced injury produced by a cortical NMDA injection in a dose-dependent manner. This reduction in injury was similar to that produced by the NMDA antagonist dizocilpine. The results indicate that isoflurane reduces excitotoxic injury. Our results are thus consistent with the premise that suppression of excitotoxicity might be one of the mechanisms by which isoflurane reduces ischemic cerebral injury.
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Acknowledgments |
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Supported by NIH Grant GMS 52098 to PMP.
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