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ANESTHETIC PHARMACOLOGY

The Effect of Prolonged Anesthesia with Isoflurane, Propofol, Dexmedetomidine, or Ketamine on Neural Cell Proliferation in the Adult Rat

Avery Tung, MD^*, Stacy Herrera, BS^*, Casimir A. Fornal, PhD, and Barry L. Jacobs, PhD

From the *Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois; Program in Neuroscience, Princeton University, Princeton, New Jersey.

Address correspondence and reprint requests to Avery Tung, MD, Associate Professor, Department of Anesthesia and Critical Care, University of Chicago. Address e-mail to atung{at}dacc.uchicago.edu.

	Abstract

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BACKGROUND: Recent evidence indicates that new neurons are produced in the adult hippocampus, and play a functional role in cognitive processes such as learning and memory. In animals, new neuron production is suppressed by increasing age, -aminobutyric acid receptor activity, reductions in basal forebrain activity and brain norepinephrine levels, and decreased environmental stimuli. Similarities between these effects and those of anesthetic administration suggest that anesthetics may modulate new cell production, and raise the possibility that postoperative cognitive dysfunction may result, in part, from anesthetic-induced suppression of adult neurogenesis. To test this hypothesis, we investigated the effects of prolonged anesthesia with four different anesthetics on hippocampal cell proliferation in young and older rats.

METHODS: Young (approximately 3 mo) and older, middle-aged (approximately 12 mo) male Sprague-Dawley rats received one of four anesthetics (propofol, isoflurane, dexmedetomidine, and ketamine) for 8 h. Rats breathed spontaneously, and anesthesia was titrated to loss of righting reflex and tolerance of clip-style pulse oximetry. Six hours into the anesthetic, rats received 200 mg/kg bromodeoxyuridine (BrdU) intraperitoneally and were killed hours later. Frozen hippocampal sections were collected and processed for BrdU using an immunoperoxidase technique. BrdU(+) cells in the dentate gyrus were then counted, and compared with unanesthetized controls to determine the degree of new cell production. All four anesthetics were given to young rats. Older rats received isoflurane and ketamine, and also received isoflurane during their dark phase.

RESULTS: Forty-two young, and 26 older, middle-aged rats were studied. When compared with controls, prolonged anesthesia in young rats with any drug had no effect on the number of BrdU(+) cells. BrdU labeling was also unaffected in older rats given isoflurane for 8 h during the light phase. Older rats had significantly lower BrdU(+) cell counts than younger rats. In older rats, ketamine anesthesia reduced BrdU(+) cell counts by 26% when compared with unanesthetized controls. Older rats given isoflurane for 8 h during their dark phase demonstrated no difference in BrdU labeling when compared with unanesthetized controls.

CONCLUSION: Despite using multiple, mechanistically distinct drugs, we found no effect of prolonged anesthesia on adult hippocampal cell proliferation in young rats, a slight suppressive effect of ketamine in older rats, and no circadian effect with isoflurane. These data indicate that anesthetics are unlikely to alter cell proliferation, and by extension that anesthetic-induced inhibition of cell proliferation is unlikely to play a major role in postoperative cognitive impairment. The contrast between our findings, current concepts of anesthetic action, and known modifiers of cell proliferation suggest an incomplete understanding of the pharmacological and behavioral factors governing new neuron production.

	Introduction

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In the mammalian brain, the genesis of new neurons has been thought to be largely absent during adulthood. Accumulating evidence, however, now indicates that a substantial number of new neurons are produced in the olfactory bulb and the dentate gyrus (DG) of the hippocampus in a variety of mammals, including humans.1,2 In the hippocampus, several studies have shown that the production of these new neurons is critical for certain types of learning and memory.3–5 Animal data have shown that hippocampal cell proliferation is altered by changes in the organism's vigilance state, environmental characteristics, and pharmacological modulation of neurotransmitters involved in arousal.6,7 Because anesthetics also affect these factors, we wondered whether anesthetics or the anesthetized state also affected adult hippocampal cell proliferation. Anesthetics also act pharmacologically on neuronal pathways involved in arousal,8 and clearly alter the impact of environmental stimuli on the organism. In addition, anesthesia and surgery are associated with cognitive changes (i.e., impaired memory, learning, and spatial orientation) that persist long after the anesthetic itself is gone.9 Together, these effects suggest a possible relationship between the anesthetized state and a reduction in hippocampal cell proliferation.

Several mechanisms may link anesthetics or the anesthetized state to new neural cell proliferation. Many anesthetics act as -aminobutyric acid (GABA) receptor agonists. In animal models, the GABA agonist muscimol acts to suppress neural cell proliferation, whereas antagonists, such as bicuculline, enhance neurogenesis.10,11 The IV anesthetic dexmedetomidine acts by reducing noradrenergic output from the locus coeruleus, and decreasing brain norepinephrine levels.12 In animals, manipulations that decrease brain norepinephrine also suppress cell proliferation.13 Inhaled anesthetics such as isoflurane inhibit the cholinergic basal forebrain,14 and chemical lesions of this area suppress hippocampal neurogenesis in animals.15 Finally, environmental stimuli may either suppress,16 or enhance,17 neural cell proliferation, depending upon their enriching or noxious qualities. Anesthetics clearly alter the perception of environmental stimuli.

Previous work examining the effect of a 4 h anesthetic with isoflurane and nitrous oxide on neural cell proliferation in adult rats found no effect.18 The methods used, however, prevent ready interpretation of these findings. In that study, the mitotic marker 5-bromo-2'-deoxyuridine (BrdU) was injected 5 min prior to anesthesia and the animals were killed 4 h later. Because BrdU has a short plasma half-life (approximately 30 min) and is incorporated into DNA during the 8 h S-phase of the cell cycle, both the timing of the BrdU injection and the duration of the anesthetic may not have been optimal for detecting anesthetic-induced changes. Moreover, because new cell production declines with age,19 effects in older rats may be more profound than those in younger ones. To better clarify the effect of anesthetics on cell proliferation, we anesthetized adult rats for 8 h (to cover the entire S-phase), administered BrdU 2 h before killing the animals, and compared the level of hippocampal cell proliferation to unanesthetized control rats. We used four mechanistically distinct anesthetics (isoflurane, propofol, ketamine, and dexmedetomidine), and performed these experiments in both young (approximately 3 mo) and older, middle-aged (approximately 12 mo) rats. In addition, we tested the effect of isoflurane in old animals in both the light (inactive) and dark (active) phases since circadian phase itself may affect cell proliferation.20

	METHODS

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This study was approved by the animal care committee at The University of Chicago and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male Sprague-Dawley rats (Harlan Industries, Indianapolis, IN) weighing 275–325 g (young, approximately 3 mo old) or 475–525 g (aged, approximately 12 mo old) were initially housed in a temperature- (21°C–24°C) and light- (12:12 h light–dark cycle with lights on at 06:00 h) controlled room with ad libitum access to food and water. A subgroup of aged rats was maintained on a reversed 12:12 h light–dark cycle (lights off at 06:00 h). All rats were adapted to their environment for a minimum of 7–10 days before experimentation. Rats scheduled to receive propofol or dexmedetomidine had an IV catheter (IITC, Woodland Hills, CA) surgically implanted as described previously21 in the internal jugular vein under ketamine (70 mg/kg, i.p.) and xylazine (6 mg/kg, i.p.) anesthesia. The catheter was tunneled subcutaneously to exit through the back of the neck.

Rats were then randomly assigned to receive one of four anesthetics: isoflurane, propofol, dexmedetomidine, and ketamine. All anesthetics were titrated to the same end-point: loss of righting reflex and ability to tolerate application of a clip-style pulse oximeter to the paw without moving. During each anesthetic, rats were allowed to breathe spontaneously; core body temperature was maintained >36°C with a heat lamp or heating pad, and continuous pulse oximetry (Ohmeda Biox 3740, Ohmeda, Madison, WI) was used to monitor heart rate and verify oxygen saturation more than 90%. For all rats, heart rate, oxygen saturation, infusion rates, rectal temperature, and rat behavior were continuously monitored and recorded every 15 min. For all drugs, anesthetic administration commenced at 07:00 h (1 h into the light phase or dark phase) and ended at 15:00 h. To replace insensible fluid losses during anesthesia, all rats (except those receiving IV anesthetics) were injected subcutaneously with 10 mL warmed saline at the beginning of the 8 h anesthetic period.

Full anesthetic details have been described previously.21,22 Rats were anesthetized as follows.

Isoflurane
Animals were placed in a 13 cm x 13 cm x 23 cm clear Lucite anesthesia chamber with a gas inlet and outlet. A compressed oxygen tank and a standard isoflurane vaporizer (Cyprane Ltd., Keighley, England, UK) were used to direct a constant 3 L/min flow of oxygen containing 1.3% isoflurane (Abbott Labs, Chicago, IL) through the box. Isoflurane levels in the chamber were monitored continuously using a Puritan-Bennett Datex model 254 airway gas monitor (Puritan Bennett, Carlsbad, CA) calibrated before each use with a reference gas containing 1.5% isoflurane (Biochem Int., Waukesha, WI).

Propofol
Briefly, animals with an indwelling internal jugular venous catheter were connected to a syringe pump (Baxter AS50, Baxter Healthcare Corp., Round Lake, IL) containing propofol (Zeneca Pharmaceuticals, Wilmington, DE) diluted to 5 mg/mL with 0.9% saline. Anesthesia was begun using a continuous infusion of propofol at 1000 µg · kg^–1 · min^–1, and continued until the righting reflex was lost and the rat was able to tolerate clip-type pulse oximetry without moving. The infusion rate was then adjusted at least every 15 min until the lowest rate compatible with the described end-point was achieved (typical maintenance dose = approximately 400 µg · kg^–1 · min^–1).

Dexmedetomidine
Rats with an indwelling jugular catheter were connected to a syringe pump (Baxter AS50, Baxter Healthcare Corp.) containing dexmedetomidine hydrochloride (Hospira, Lake Forest, IL) diluted to 10 µg/mL with 0.9% saline. Sedation was initiated using a continuous infusion of dexmedetomidine at approximately 3 µg · kg^–1 · min^–1, and continued until the righting reflex was lost and the rat was able to tolerate clip-type pulse oximetry without moving. The infusion rate was then adjusted at least every 15 min until the lowest rate compatible with the described end-point was achieved (approximately 0.5 µg · kg^–1 · min^–1).

Ketamine
Rats were anesthetized via IM injections of ketamine hydrochloride (Lloyd Laboratories, Shenandoah, IA) at an initial dose of 75 mg/kg. Injections were repeated at similar doses whenever animals began to move spontaneously or refused to tolerate clip-type pulse oximetry (typically every 1–3 h).

BrdU Administration and Animal Perfusion
After 6 h of continuous anesthesia as described above, all rats received a single intraperitoneal injection of 200 mg/kg of BrdU (Sigma-Aldrich, St. Louis, MO) dissolved in 0.9% saline containing 0.007 N NaOH. After 8 h of anesthesia, and 2 h after BrdU injection, rats were given a mixture of intraperitoneal ketamine hydrochloride (70 mg/kg) and sodium pentobarbital (20 mg/kg) and perfused transcardially with ice-cold physiological saline, followed by paraformaldehyde (4% in 0.1 M phosphate buffer, pH 7.5). Brains were removed, postfixed in paraformaldehyde for 24 h at 4°C, and then transferred to sucrose (30% in 0.1 M phosphate-buffered saline, PBS) until sectioned.

BrdU Immunohistochemistry
Frozen coronal sections (40 µm) were cut through the entire hippocampus and every 12th section was processed for BrdU using a slide-mounted immunoperoxidase technique.23

Briefly, sections were mounted onto adhesive microscope slides (Superfrost® Plus Gold, Erie Scientific CO, Portsmouth, NH), dried overnight at 37°C, boiled in citric acid (0.01M, pH 6.0) for 7 min, and allowed to cool for 20 min. The tissue sections were then digested with trypsin (0.1% in 0.1M Tris buffer, pH 7.5, containing 0.1% CaCl₂) for 8.5 min, denatured with 2.4 N HCl (in PBS) for 30 min, and then incubated with a mouse monoclonal antibody raised against BrdU (NCL-BrdU; Novocastra Laboratories Ltd., Newcastle upon Tyne, UK) in PBS (1:200; containing 0.5% Tween-20) for 24 h at 4°C. The next day, sections were incubated with a biotinylated horse anti-mouse IgG (1:200 in PBS; Vector Laboratories, Burlingame, CA) and with avidin-biotin-horseradish peroxidase complex (1:100 in PBS; Vectastain® Elite ABC kit, Vector Laboratories) for 60 min, and then reacted with 3,3'-diaminobenzidine and urea hydrogen peroxide (Sigma- Aldrich) in deionized water for 10 min, to visualize labeled cells. Sections were then counterstained with cresyl violet, dehydrated and coverslipped under DPX (Fluka BioChemika, Steinheim, Switzerland).

Data Analysis
All slides were analyzed blindly with respect to treatment condition, using an Olympus BX-60 light microscope (Olympus America Inc., Melville, NY). In every 12th section throughout the hippocampus, BrdU+ cells (stained dark brown) were counted bilaterally in the DG at 400x magnification. The cell counts for each animal were summed across all sections and then multiplied by 12 (inverse of the section sampling fraction) to obtain an estimate of the total number of BrdU+ cells in the DG. In addition, the DG was divided into anterior (dorsal) and posterior (ventral) portions, using the criteria of Guzmán-Marín et al.24 Briefly, the boundary separating the anterior and posterior portions of the DG corresponded to the region where the CA2 and CA3 pyramidal cell layers coalesce into a continuous cell layer in the coronal plane [approximately –4.5 mm from Bregma, according to the atlas of Paxinos and Watson25]. Typically, there were six anterior and four posterior sections containing the DG for each animal.

For statistical comparisons among treatment groups, either a two-tailed unpaired t-test or a one-way analysis of variance was used, followed by post hoc Newman–Keuls multiple comparison test. Data were expressed as means ± sd. A probability value <0.05 was considered statistically significant.

	RESULTS

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Sixty-eight animals were studied: 42 young (approximately 3 mo old) and 26 aged (approximately 12 mo old) rats. At the time of anesthesia, the mean body weight and age of the young rats was 307 ± 19 g and 79 ± 15 days, respectively, compared with 513 ± 44 g and 389 ± 16 days for the group of aged rats. Table 1 shows cumulative anesthetic doses for all groups. Of the 42 young animals, 29 received anesthesia (12 isoflurane, 7 propofol, 6 ketamine, and 4 dexmedetomidine) and 13 served as controls (no anesthesia). Of the 26 aged animals, 14 received anesthesia (10 isoflurane and 4 ketamine) and 12 served as controls (no anesthesia). In addition to studying the effect of isoflurane anesthesia during the light phase (as was done for all the other anesthetics), half of the aged isoflurane (n = 5) and control (n = 6) animals were studied during the dark (active) phase. Proprofol and dexmedetomidine were not given to older rats because prolonged anesthesia with these drugs proved too difficult to maintain consistently.

In young rats, no significant differences in BrdU labeling were found between control animals and those anesthetized with isoflurane (P = 0.806), ketamine (P = 0.178), propofol (P = 0.945), or dexmedetomidine (P = 0.636) (Tables 2 and 3). The mean number of BrdU+ cells was slightly increased (13%) in the dexmedetomidine group and slightly reduced (12%) in the ketamine group, compared with their respective controls. For the other two anesthetics (isoflurane and propofol), mean BrdU cell counts were within 2% of control values. We found no correlation between average or total drug dose and BrdU cell counts or change from control BrdU values for propofol, dexmedetomidine, or ketamine.

No differences in basal levels of BrdU labeling were found between aged animals killed during the dark phase and those killed during the light phase (818 ± 105 vs 840 ± 142, respectively; P = 0.767). When aged animals were anesthetized with isoflurane during the dark phase, no significant effect on BrdU labeling was found when compared with controls (720 ± 173 vs 840 ± 142, respectively; P = 0.236) (Table 4). No other regional differences (anterior versus posterior DG) were found for any of the other anesthetic drugs studied (data not shown).

	DISCUSSION

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This study has two primary findings. First, despite using multiple, mechanistically distinct drugs, we found no effect of prolonged anesthesia on adult hippocampal cell proliferation in young (approximately 3 mo old) Sprague-Dawley rats. Along with a similar lack of effect in older (approximately 12 mo) rats, these results do not support the hypothesis that anesthetic-induced inhibition of cell proliferation plays a role in postoperative cognitive changes. Although the present study only examined effects of anesthesia on proliferation and not cell differentiation, a single exposure to anesthesia that did not affect proliferation would be unlikely to subsequently alter neurogenesis. Our second finding is that in aged rats anesthetized during their light phase, the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine suppressed cell proliferation. This observation implies a possible effect of ketamine on postoperative cognitive changes.

The lack of effect seen with prolonged anesthesia has been observed before,18,26 but is not consistent with the known pharmacology of both anesthetics and neural cell proliferation. Via agonist effects on GABA receptors, suppression of brain norepinephrine output, and/or reductions in basal forebrain activity, anesthetics would be pharmacologically expected to suppress cell proliferation. One hypothesis for the absence of such suppression may be that the anesthetized state exerts both enhancing, and suppressing effects on hippocampal cell proliferation. Enriching environmental stimuli enhances new cell proliferation in animals,17 whereas stressful stimuli such as restraint or sleep deprivation are suppressive.16,23 In addition, cell proliferation is increased during the light phase when external stimuli are suppressed due to naturally occurring sleep.20,27 By creating a vigilance state similar to sleep, anesthetics may thus have a similar, enhancing effect that offsets any suppressive effect they have pharmacologically.

With one exception, our findings in young rats were replicated in older ones. Overall, the number of BrdU-labeled cells in older rats was only 25% of the values we found in younger animals. This reduction is consistent with other reports,19 and supports our use of middle-aged rats to model aged humans. In aged rats anesthetized during the light phase with ketamine, we found a small, but significant decrease in BrdU labeling, even though these animals received less ketamine than the young animals. These data suggest that unlike other anesthetics, ketamine may suppress neural cell proliferation, and that aged animals may be more sensitive to these effects.

An effect of ketamine different from other anesthetics is consistent both with its effect on adrenal activity and its known mechanism of action. Unlike most other anesthetics, ketamine anesthesia increases adrenocortical activity28 and does not act at GABA receptors.29 Rather, ketamine is a noncompetitive antagonist of the NMDA receptor, and an indirect antagonist at the phencyclidine binding site.30 Because ketamine increases neurogenesis in adult rats,31 as does the NMDA receptor antagonist CGP-43487,32 ketamine anesthesia should thus enhance cell proliferation. Instead, we found a paradoxical suppressive effect in aged rats only. This effect is pharmacologically unexpected and suggests either a yet unknown direct effect of ketamine, or a larger role for behavioral than for pharmacological effects on cell proliferation.

Our observations imply an effect of age on the relationship between ketamine and cell proliferation. One possibility is the relationship between age and adrenocortical function. Feedback inhibition of steroid secretion is impaired in elderly rats,33 suggesting that a modulator of steroid secretion such as ketamine may have a larger impact in older animals. The lack of an age effect with isoflurane also supports a steroid-based mechanism linking ketamine to cell proliferation since isoflurane anesthesia does not alter steroid homeostasis.

Our study has limitations. Although we found no difference between control and any type of anesthesia in young rats (or old rats anesthetized with isoflurane), our small numbers raise the possibility of type II error. We feel such a possibility unlikely. Our results are consistent with other literature reports also finding no anesthetic effect.18,26 In addition, the magnitude of any difference identified with an increased sample size would have been smaller than differences observed with other known modulators of neurogenesis.6 Because of the lack of measurable end-points for anesthetic depth, we did not explore the effect of depth of anesthesia on cell proliferation. It is likely, however, that smaller anesthetic doses would have resulted in rat movement, and larger doses would have caused cardiorespiratory depression that itself might have affected cell proliferation. Moreover, the lack of correlation between drug dose and BrdU counts for any of the anesthetics we examined suggests little variation with anesthetic dose. Because ketamine was administered by IP bolus, variability in drug levels may have obscured an enhancing or suppressing effect. Because we did not control ventilation, CO₂ levels may have been higher in anesthetized animals. We do not believe that failing to control for CO₂ masked an anesthetic effect on cell proliferation as no current evidence links either hypercapnia or acidosis to hippocampal cell proliferation. Moreover, anesthetic-induced hypercapnia would likely increase stress and suppress neurogenesis. We also did not determine whether newly formed cells differentiated into neurons or glia. Because 80%–90% of new cells ultimately become neurons, we believe that most new cells are likely to be cognitively important. Finally, our "aged" rats were only 12 mo old. It is possible that differences may have been larger with even older rats but the risks of cardiorespiratory compromise with anesthesia in these older animals, and the pronounced decrease in BrdU labeling with age, made such a task technically unfeasible.

In summary, we found no effect of prolonged (8 h) anesthetics during the light or dark phase with isoflurane, propofol, or dexmedetomidine on hippocampal cell proliferation in 3 or 12-mo-old Sprague-Dawley rats. We did find small, suppressive effects of ketamine in old, but not in young rats. These unexpected results suggest that the sum of the many potential mechanisms linking cell proliferation to the anesthetized state (vigilance state, environmental stimuli, adrenal effects of anesthesia, direct pharmacologic effects), result in no overall effect. Clinically, our results imply that suppression of adult hippocampal cell proliferation is unlikely to be an effect of brief or prolonged anesthesia, and thus unlikely to cause postoperative cognitive dysfunction in humans. Further work is necessary to clarify the relevance of pharmacological and behavioral modulation on new neuron production.

	ACKNOWLEDGMENTS

 
We thank Jessica Barson, Claire Gutierrez, Joanne Stevens, and Sherry Zhang for their excellent technical assistance.

	Footnotes

 
Accepted for publication January 31, 2008.

Supported by National Institutes of Health grants #K08-GM000697 (A.T.), Bethesda, MD, the Brain Research Foundation at the University of Chicago, and the University of Chicago Department of Anesthesia and Critical Care, Chicago, IL.

Presented, in part, on October 14 at the 2006 meeting of the American Society of Anesthesiologists, Chicago, IL.

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