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Anesth Analg 2001;92:362-368
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Xenon Inhibits but N2O Enhances Ketamine-Induced c-Fos Expression in the Rat Posterior Cingulate and Retrosplenial Cortices

Atsushi Nagata, MD, Shin-ichi Nakao, MD, PhD, Nobuyasu Nishizawa, MD, Munehiro Masuzawa, MD, Takefumi Inada, MD, Kohei Murao, MD, Etsuko Miyamoto, MD, and Koh Shingu, MD, PhD

Department of Anesthesiology, Kansai Medical University, Osaka, Japan

Address correspondence and reprint requests to Shin-ichi Nakao, Department of Anesthesiology, Kansai Medical University, Moriguchi, Osaka 570-8507, Japan. Address e-mail to nakaos{at}takii.kmu.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Both nitrous oxide (N2O) and xenon are N-methyl-D-aspartate receptor antagonists that have psychotomimetic effects and cause neuronal injuries in the posterior cingulate and retrosplenial cortices. We investigated the effect of xenon, xenon with ketamine, N2O, and N2O with ketamine on c-Fos expression in the rat posterior cingulate and retrosplenial cortices, a marker of psychotomimetic effects. Brain sections were prepared, and c-Fos expression was detected with immunohistochemical methods. A loss of microtubule-associated protein 2, a marker of neuronal injury, was also investigated. The number of Fos-like immunoreactivity positive cells by ketamine IV at a dose of 5 mg/kg under 70% N2O (128 ± 12 cells per 0.5 mm2) was significantly more than those under 30% (15 ± 2 cells per 0.5 mm2) and 70% xenon (2 ± 1 cells per 0.5 mm2). Despite differences in c-fos immunoreactivity, there was no loss of microtubule-associated protein 2 immunoreactivity in any group examined. Xenon may suppress the adverse neuronal effects of ketamine, and combined use of xenon and ketamine seems to be safe in respect to neuronal adverse effects.

Implications: Xenon may suppress adverse neuronal effects of ketamine. Conversely, combined use of N2O and ketamine may increase the risk of neuronal adverse effects, such as psychotomimetic effects.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Xenon is an inert gas and has anesthetic properties (1). Its minimum alveolar concentration (MAC) is approximately 71% in humans (2), suggesting that it is more potent than nitrous oxide (N2O). Because it has a very low blood-gas partition coefficient (0.14), the induction of and emergence from xenon anesthesia is quite rapid (3,4). It is nonexplosive, nontoxic, nonpungent, extremely unreactive, and environmentally friendly (5).

Both N2O (6) and xenon (7) are noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists. Despite neuroprotective properties, NMDA receptor antagonists have psychotomimetic effects in humans and cause abnormal locomotor activities in rodents (8,9). They also cause either reversible or, in certain circumstances, irreversible neuronal damage in the rat posterior cingulate and retrosplenial cortices (PC/RS), which are thought to be the brain regions responsible for their psychotomimetic activity (8,10). Jevtovic-Todorovic et al. (6) have demonstrated that N2O itself causes neuronal damage in the PC/RS at larger concentrations (50% effective concentration for producing neurotoxic effects in the rat is 117 vol%). Thus, it is possible that the combined use of NMDA receptor antagonists, such as ketamine (11) and N2O or ketamine and xenon, would exacerbate the neuronal adverse effects, such as psychotomimetic activities and neurotoxicity, of either NMDA receptor antagonist alone.

We investigated the expression of c-Fos, the protein encoded by the c-fos gene, in the rat PC/RS after treatment with xenon alone, N2O alone, and the combined use of xenon or N2O with ketamine, because c-Fos expression PC/RS induced by NMDA receptor antagonists is a reliable marker of their psychotomimetic activities (12,13) and, in certain circumstances, neurotoxicity (14,15). A loss of microtubule associate protein 2 (MAP2) immunoreactivity in the PC/RS was also investigated for a direct observation of neuronal injuries.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by the Animal Research Committee of Kansai Medical University. All experiments were performed on male Wistar rats weighing 280–380 g.

Experimental Model 1 (Rats Under Mechanical Ventilation)
Twenty-five rats were assigned to five groups. In Group 1 (N2O alone, n = 5), rats were first anesthetized with 3% sevoflurane in 70% N2O and 30% oxygen. The right femoral artery was cannulated for the measurement of arterial blood pressure and sampling of blood for gas analysis. The tail vein was cannulated for the administration of fluids and drugs. Tracheotomy was performed, and mechanical ventilation was performed by using an animal respirator with the aid of pancuronium. End-tidal CO2 was maintained at 30–35 mm Hg throughout the experiment. Sevoflurane was stopped, and 20 µg/kg of fentanyl was administered IV. Thirty minutes after the cessation of sevoflurane, when the concentration of sevoflurane was almost 0, sterilized saline (0.9% NaC1) was injected IV. In Group 2 (N2O with ketamine, n = 5), the experimental conditions were the same as for Group 1, but 5 mg/kg of ketamine was injected instead of saline. In Group 3 (70% xenon alone, n = 5), the experimental conditions were the same as for Group 1, but after tracheotomy, sevoflurane and N2O were stopped, and anesthesia was maintained with both 70% xenon and 30% oxygen instead of N2O and oxygen. Thirty minutes after the start of xenon, when the concentrations of both N2O and sevoflurane were almost 0, sterilized saline was injected IV. In Group 4 (70% xenon with ketamine [n = 5]), the experimental conditions were the same as for Group 3, but 5 mg/kg of ketamine was injected IV instead of sterilized saline. In Group 5 (30% xenon with ketamine [n = 5]), the experimental conditions were the same as for Group 4, but anesthesia was maintained with 30% xenon instead of 70% xenon.

The xenon concentration was continuously monitored with a xenon gas monitor (Anzai Sogyo, Tokyo, Japan). Sevoflurane and N2O concentrations were continuously monitored with an anesthetic gas monitor, Type 1304® (Brüel & Kjær, Nærum, Denmark). A rectal thermometer was inserted, and the temperature was maintained at 37–38°C by using a warm-water mattress and a heating lamp.

Experimental Model 2 (Rats Under Spontaneous Respiration)
To investigate the effect of ketamine alone, and whether N2O failed to inhibit or enhanced the ketamine-induced c-Fos expression in the PC/RS, another five groups were studied. In Group 6 (control group, n = 5), rats received sterilized saline (0.9% NaC1) intraperitoneally (IP). In Group 7 (n = 5), rats received 100 mg/kg ketamine IP. In Group 8 (n = 5), after being placed in a plastic cage (30 x 30 x 25 cm) with sawdust flooring continuously insufflated with 70% N2O and 30% oxygen for 15 min, the rats received sterilized saline IP and were placed in the same cage for another 2 h. In Group 9 (n = 5), the experimental conditions were the same as for Group 8, but 100 mg/kg ketamine was injected instead of saline. In Group 10 (n = 5), the experimental conditions were the same as for Group 9, but 30% xenon and 70% oxygen were continuously insufflated instead of N2O and oxygen.

Two hours after injection of ketamine or saline, the rats were deeply anesthetized with sevoflurane. They were perfused transcardially, initially with ice-cold 0.01M phosphate-buffered saline (PBS) (0.9% NaC1 in 0.01M phosphate buffer, pH 7.4) and subsequently with a fixative solution containing 4% paraformaldehyde, 0.2% picric acid, and 0.35% glutaraldehyde in 0.1M phosphate buffer (PB), pH 7.4. The brain was quickly removed from the skull and immersed for 1 day in a postfixative solution containing 4% paraformaldehyde and 0.2% picric acid in 0.1M PB at 4°C. The brain was then placed in 0.1M PB containing 15% sucrose and 0.1% sodium azide at least until it sank. The brain was frozen and cut into 20-µm-thick coronal sections in a cryostat. The sections were immersed in 0.1M PBS at 4°C. Twenty coronal sections per animal were made at the plane of approximately interaural 6.2 mm. From these sections, three sections were selected at every three sections and subjected to the immunohistochemical procedure.

Unless otherwise stated, all incubations were performed at room temperature. The sections were incubated with a polyclonal anti-c-fos antibody (Oncogene Science Inc, Uniondale, NY) at a dilution of 1:2000 in 0.1M PBST (0.1M PBS containing 0.3% Triton X-100) at 4°C for 4 days. The sections were washed three times with 0.1M PBST, 10 min per wash, and incubated with biotinylated antirabbit antibody (1:1000 dilution in 0.1M PBST; Vector Laboratories, Burlingam, CA) for 1.5 h. After washing, the sections were incubated with an avidin-biotin-peroxidase complex (1:800 dilution in 0.1M PBST, Vector Laboratories) for 1.5 h. The sections were then reacted with a solution containing 0.0045% H2O2, 0.2% 3,3'-diaminobenzidine 4HCl, and 0.3% nickel ammonium sulfate in 0.05M Tris-HCl, pH 7.6, for 5 min. Immunohistochemically detected nuclear-associated reaction product was referred to as Fos-like immunoreactivity (Fos-LI). To confirm the specificity of immunostaining, some sections were incubated with anti-c-fos antibody preabsorbed with an excess of the peptide against which the antibody was raised and shown to yield no cellular-specific reaction product.

MAP2 immunoreactivity was detected for three slices in all groups. Staining conditions were almost the same as for c-Fos staining, but a monoclonal anti-MAP2 antibody (1:10,000 dilution in 0.1M PBST; Sigma Chemical Company, St. Louis, MO) was used for a primary antibody, and biotinylated antimouse antibody (1:500 dilution in 0.1M PBST; Vector Laboratories) was used for a second antibody.

Quantification of c-fos expression was performed with respect to the number of Fos-LI positive boutons in a unit area of 0.5 mm2 in the same brain regions (PC/RS) per section with a computer-assisted image analysis system (Mac ASPECT/PPC; Mitani Co., Tokyo, Japan) attached to a light microscope at 100x magnification and a high-resolution color video camera. Neurons with darkly stained nuclei were counted as immunoreactive. The Fos-LI-positive boutons were counted bilaterally in three sections for each rat.

The MAP2 staining-positive area in a unit area of 0.0613 mm2 (the density of MAP2 staining dendrites) in the PC/RS was determined with a computer-assisted image analysis system (Mac ASPECT/PPC; Mitani Co.) attached to a light microscope at 500x magnification and a high-resolution color video camera. The number of Fos-LI positive boutons and the positive area of MAP2 staining were observed by an observer blinded as to the treatment group.

Physiological data were analyzed by one-way analysis of variance. Post hoc differences among groups were identified by Bonferroni’s t-test. We counted the Fos-LI positive boutons and MAP2 staining positive area in three sections per animal, the mean of which represented the number for each individual animal. The number of Fos-LI positive boutons in a 0.5-mm2 area of each group was expressed as mean ± SEM (n = 5 in each group). The MAP2 staining positive area in a unit area of 0.0613 mm2 in the PC/RS was determined and expressed as mean ± SEM (n = 5 in each group). Statistical comparison among groups, Groups 1 to 5 and Groups 6 to 10, was performed, respectively, by analysis of variance and Bonferroni’s modification of the t-test. Differences at P < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The physiological values in Groups 1 to 5 are shown in Table 1. The PaO2 was significantly increased in Group 5 compared with that in other groups because of the increased concentration of inhaled oxygen.


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  		Table 1. Physiological Values
 
Figure 1 shows a schematic experimental time line of Groups 4 and 5. A small number of Fos-LI positive boutons (17 ± 6) were observed in the PC/RS under 70% N2O alone ( Fig. 2 and 3). No Fos-LI was observed under 70% xenon (Fig. 2 and 3). Marked Fos-LI was observed in the PC/RS by 5 mg/kg ketamine IV under 70% N2O (Fig. 2 and 3). However, ketamine-induced Fos-LI in the PC/RS was significantly less under xenon anesthesia (Fig. 2 and 3). The number of Fos-LI positive boutons in the PC/RS in Group 5 (30% xenon with 5 mg/kg ketamine) was 15 ± 2, and, in Group 4, 2 ± 1 (70% xenon with 5 mg/kg ketamine).



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  		Figure 1. A schematic experimental time line of Groups 4 and 5.

 


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  		Figure 2. Fos-like immunoreactivity in the rat posterior cingulate and retrosplenial cortices 2 h after 5 mg/kg ketamine or saline IV. A, Group 1 (70% N2O alone). B, Group 2 (70% N2O with ketamine). C, Group 3 (70% xenon alone). D, Group 4 (70% xenon with ketamine). Bar = 100 µm.

 


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  		Figure 3. The number of Fos-like immunoreactivity (Fos-LI) positive boutons in 0.5 mm2 of the posterior cingulate and retrosplenial cortices (PC/RS) in Groups 1 to 5. Xenon inhibits the number of ketamine-induced Fos-LI boutons in the PC/RS and alone does not induce the Fos-LI. Conversely, N2O fails either to inhibit or enhance the Fos-LI. Data are expressed as mean ± SE (n = 5). *P < 0.05 versus Group 2 (70% N2O with ketamine 5 mg/kg IV).

 
Figure 4 shows the number of Fos-LI positive boutons in the PC/RS of Groups 6 to 10. No Fos-LI was observed in the control group (Group 6). Ketamine 100 mg/kg IP induced moderate Fos-LI (60 ± 10). A small number of Fos-LI positive boutons were observed under 70% N2O alone (22 ± 6), and 70% N2O significantly enhanced the ketamine-induced Fos-LI (116 ± 13). Thirty percent xenon significantly reduced ketamine-induced Fos-LI (19 ± 2).



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  		Figure 4. The number of Fos-like immunoreactivity positive boutons in 0.5 mm2 of the posterior cingulate and retro-splenial cortices (PC/RS) in Groups 6 to 10, 2 h after saline or ketamine injection. N2O significantly enhances the number of ketamine-induced Fos-LI boutons in the PC/RS, whereas xenon significantly inhibits it. Data are expressed as mean ± SE (n = 5). *P < 0.05 versus Group 9 (70% N2O with ketamine 100 mg/kg IP). §P < 0.05 versus Group 7 (ketamine 100 mg/kg IP). #P < 0.05 versus Group 6 (control).

 
The MAP2 staining positive area in a unit area of 0.0613 mm2 of Group 1 to Group 5 was 0.0258 ± 0.004 mm2, 0.0250 ± 0.006 mm2, 0.0354 ± 0.004 mm2, and 0.0254 ± 0.010 mm2, respectively, and Group 6 to Group 10 was 0.0256 ± 0.010 mm2, 0.0253 ± 0.003 mm2, 0.0265 ± 0.011 mm2, 0.0255 ± 0.008 mm2, and 0.0260 ± 0.010 mm2, respectively. There was no statistically significant difference among groups, i.e., no loss of MAP2 immunoreactivity in the PC/RS was observed in any group. Figure 5 shows the representative MAP2 immunoreactivity in the PC/RS in xenon alone and ketamine or ketamine with N2O administration groups in which marked c-Fos expression was observed.



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  		Figure 5. MAP2 immunoreactivity in the rat posterior cingulate and retrosplenial cortices (PC/RS) 2 h after ketamine administration. A, Group 2 (70% N2O with ketamine). B, Group 3 (70% xenon alone). C, Group 7 (ketamine alone). D, Group 9 (70% N2O with ketamine). Filamentous structures show dendritic neurites, and the presence of the protein was also observed in neuronal somata. No loss of MAP2 immunoreactivity in the PC/RS was observed. Bar = µm.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We demonstrated that xenon did not induce Fos-LI in the PC/RS and that xenon significantly and dose-dependently inhibited ketamine-induced Fos-LI in the PC/RS. However, a small amount of Fos-LI was observed in the PC/RS even under 70% N2O alone, and N2O enhanced ketamine-induced Fos-LI in the PC/RS. This is the first report that demonstrated the opposite effects of xenon and N2O, both of which are NMDA receptor antagonists.

Several potential limitations of our model should be considered. First, we compared the effects of 70% and 30% xenon, and 70% N2O. The MAC value of xenon in rats is not available yet but is 71% in humans (2). Seventy percent xenon is approximately 1 MAC and 30% xenon is approximately 0.43 MAC in humans, whereas 70% N2O is approximately 0.45 MAC in rats (16) and 0.7 MAC in humans (17). The concentration of N2O we used was the median of the two concentrations of xenon on a human MAC basis. Second, because almost all anesthetics have {gamma}-aminobutyric acid (GABA)-ergic activity and inhibit ketamine-induced Fos-LI in the PC/RS (18), we could not use any of them for baseline anesthesia for mechanical ventilation. Sevoflurane was used only for cannulation and tracheotomy because of its low blood/gas partition coefficient, and it was stopped 30 minutes before ketamine or saline injection. Still, there is a possibility that the remaining sevoflurane in the brain would suppress the c-Fos expression to a certain extent, even though end-tidal concentration of sevoflurane was zero. However, even though an individual animal would be influenced by the remaining sevoflurane, our net results were not influenced because sevoflurane was used for all groups in Experimental Model 1. Furthermore, we studied another five groups, in which rats were kept under spontaneous breathing, to neglect the effects of sevoflurane and investigate the effect of ketamine alone of c-Fos expression in the PC/RS and whether N2O enhanced the ketamine-induced c-Fos expression. Third, fentanyl was added to reduce the stress of rats against mechanical ventilation, but our net results were not affected by fentanyl because it was used for all groups in Experimental Model 1, even if an individual animal would be affected. Moreover, the effect of fentanyl was neglected in Experimental Model 2.

Usually, c-fos is expressed rapidly and transiently in response to a variety of extracellular stimuli-induced increases in intracellular calcium and cAMP (19). It acts as a "third messenger" molecule in signal transduction systems, where it couples short-term signals to long-term adaptive modification by regulating the pattern of gene expression (19). Expression of c-fos is a good metabolic marker (20) and is widely used to map pathways involved in the spread of epileptic seizures and noxious stimuli. Furthermore, recent studies have revealed that c-fos expression in specific brain regions plays a role in functional output: systemic administration of cocaine induces c-fos expression in the nucleus accumbens implied in rewarding and locomotor stimulant properties of several drugs of abuse, including cocaine. Bilateral administration of antisense oligonucleotides against c-fos in the nucleus accumbens blocks not only c-fos expression but also cocaine-induced locomotor stimulation, without affecting spontaneous exploratory activity (21). Systemic administration of D-amphetamine produces an increase in random locomotor activity and induces a dramatic increase in c-fos expression in the bilateral striata. Unilateral attenuation of D-amphetamine-induced c-fos expression by antisense oligonucleotides against c-fos in the striatum results in a directed rotation behavior (22). As for NMDA receptor antagonists, c-fos expression by NMDA receptor antagonists is closely related to their behavioral effects, psychotomimetic effects, or both and is a reliable marker of the effects (12,13). Some reports also indicate that NMDA receptor antagonist-induced c-fos expression in the PC/RS might indicate neuronal injuries (14,15). MAP2 is located almost exclusively in neuronal perikarya and dendrites, and it binds to and stabilizes microtubules and may help to regulate microtubule spacing (23). A loss of MAP2 indicates neuronal injuries and thus is used as a rather sensitive and reliable marker of neuronal injuries (24–26).

Ketamine is a widely used IV anesthetic and a noncompetitive NMDA receptor antagonist (11). Both N2O (6) and xenon (7) are NMDA receptor antagonists. Olney et al. (8) demonstrated that NMDA receptor antagonists, such as phencyclidine, ketamine, and MK801, induced reversible neuronal vacuole formation in the PC/RS and that muscarinic M1 antagonists or diazepam and barbiturates blocked this neuronal injury. Sharp et al. (27) demonstrated that haloperidol, a dopamine and sigma receptor blocker, prevented the induction of heat shock protein 70 by noncompetitive NMDA receptor antagonists in the PC/RS. They suggested that the PC/RS is the brain region responsible for NMDA receptor antagonist-induced psychotomimetic activity and schizophrenia. We previously demonstrated that ketamine induced marked Fos-LI in the PC/RS (28), which was inhibited by halothane, diazepam, and propofol, probably through GABAA receptor activation (18,29,30). In the present study, even 70% N2O alone induced a small amount of Fos-LI in the PC/RS. Furthermore, N2O significantly enhanced the ketamine-induced Fos-LI, and a combination of ketamine and 70% N2O induced marked Fos-LI. Thus, the combination of ketamine and N2O, without another anesthetic that has GABAA activating property, might exacerbate the side effects of either NMDA receptor antagonist alone, especially neuronal adverse effects such as psychotomimetic activity, neurotoxicity, or both. Conversely, xenon not only induced no Fos-LI in the PC/RS, but also significantly inhibited the ketamine-induced Fos-LI. These results suggest that either xenon alone or the combined use of xenon and ketamine may be safe in respect to neuronal adverse effects. Our results are consistent with the fact that emergence from xenon anesthesia is not only fast but also smooth and without exhibited agitation or restlessness (4). No disruption of MAP2 structure was observed in the PC/RS in Groups 1 to 10. The finding suggests that the neurons in the PC/RS might escape injuries or that the neuronal injuries, if any, are slight or reversible. However, we should still be aware of the risk that marked c-Fos expression; it indicates marked neuronal activation and induction of psychotomimetic activities and suggests neuronal plastic changes.

Further studies will be required to elucidate the mechanism of an opposite neuronal effect of N2O and xenon shown in the present study. We suggest that xenon may have effects on receptors or channels other than NMDA receptors, though reliable data have not been reported.

In conclusion, we demonstrated that xenon inhibited ketamine-induced c-Fos expression in the PC/RS, whereas N2O enhanced the c-Fos expression. Although the findings of the current investigation may not be generalizable to patients, they suggest that not only xenon alone, but also xenon with ketamine, may be safe in respect to neuronal adverse effects; however, the combined use of N2O with ketamine, without another anesthetic that has GABAA activating properties, might exacerbate the neuronal adverse effects found with use of ketamine or N2O alone.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 4, 2000.




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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 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press