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Kaohsiung Journal of Medical Sciences (2016) xx, 1e4

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.kjms-online.com

ORIGINAL ARTICLE

Effect of day/night administration of three different inhalational anesthetics on melatonin levels in rats Elvan Ocmen a,*, Hale Aksu Erdost a, Leyla S. Duru a, Pinar Akan b, Dilek Cimrin b, Ali N. Gokmen a a b

Department of Anesthesiology, Dokuz Eylul University, Izmir, Turkey Department of Biochemistry, Dokuz Eylul University, Izmir, Turkey

Received 11 January 2016; accepted 29 April 2016

KEYWORDS Circadian rhythm; Desflurane; Isoflurane; Melatonin; Sevoflurane

Abstract The nocturnal peak of melatonin can be altered after anesthesia and surgery. We aimed to examine the melatonin levels during the day and night after anesthesia with three commonly used inhalational anesthetics. Forty-eight male Wistar albino rats were randomized into eight groups. Rats were administered anesthesia between 7:00 AM and 1:00 PM (day groups) or 7:00 PM and 1:00 AM (night groups) for 6 hours. At the end of the anesthesia, blood samples were collected for assessing melatonin levels. Mean values of melatonin levels after 6 hours of anesthesia during daytime were 43.17  12.95 for control, 59.79  27.83 for isoflurane, 50.75  34.28 for sevoflurane and 212.20  49.56 pg/mL for desflurane groups. The night groups’ mean melatonin levels were 136.12  33.20 for control, 139.85  56.29 for isoflurane, 117.48  82.39 for sevoflurane and 128.70  44.63 pg/mL for desflurane groups. Desflurane anesthesia between 7:00 AM and 1:00 PM significantly increased melatonin levels (p < 0.001). Sevoflurane and desflurane anesthesia between 7:00 PM and 1:00 AM decreased the melatonin levels but there were no significant differences (p Z 0.904 and p > 0.99, respectively). Isoflurane anesthesia did not significantly change melatonin levels during day or night (p Z 0.718 and p > 0.99, respectively). Our results demonstrate that during daytime desflurane anesthesia can alter melatonin levels. Altered melatonin rhythm following inhalational anesthesia can be related to sleep disorders observed after anesthesia. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Anesthesiology, Dokuz Eylu ¨l University School of Medicine, 35340 Inciralti, Izmir, Turkey. E-mail address: [email protected] (E. Ocmen). http://dx.doi.org/10.1016/j.kjms.2016.04.016 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Ocmen E, et al., Effect of day/night administration of three different inhalational anesthetics on melatonin levels in rats, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.04.016

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Introduction Melatonin is a hormone that has a nocturnal peak. Melatonin secretion is controlled by suprachiasmatic nuclei (SCN), which has a circadian clock regulated by day/night cycles. Reduced or asynchronous melatonin levels can be associated with aging of the organism and depression [1,2]. It is also known that melatonin regulates the sleep/wake cycles [2,3] so the influences of this hormone’s rhythm can be responsible for sleep disturbances, drowsiness, fatigue and delirium after anesthesia and surgery [4]. General anesthesia is a sleepeawake condition which is thought to alter circadian rhythms. It has been shown that anesthesia with or without surgery can influence the circadian rhythm of melatonin [1,5e7]. We previously found that in 15-day-old rats the administration of isoflurane during the day increases melatonin levels while administration at night has no effect [8]. Likewise, sevoflurane anesthesia during day and night hours increases melatonin levels in 15-day-old rats (unpublished observations). We hypothesized that day administration of inhalational anesthetics could alter the circadian rhythm of melatonin but night administration could conserve this rhythm. The aim of this experimental study was to investigate the effects of the three commonly used inhalational anesthetics: sevoflurane, isoflurane and desflurane, on melatonin levels administered over day/night cycles.

Methods After the approval of the ethics committee of Dokuz Eylul University (approval no: 09/2013), 48 male Wistar albino rats weighted between 200e250 g were included in this experimental study. Until the experiment, the subjects were kept under standard laboratory conditions (12 hours lighte12 hours dark, 20e22o C and 50e60% humidity). All efforts to reduce the number of animals and their suffering were made. Rats were randomized into control and anesthesia groups. Desflurane (Desfluran, Abbott Laboratories, Istanbul, Turkey), sevoflurane (Sevofluran, Vapor 19.1, Abbott Laboratories, Wiesbaden, Germany) and isoflurane (Forane, Abbott Laboratories, Istanbul, Turkey) were used for anesthesia. Night groups inhaled 6 L/min oxygen (control) or 1 minimum alveolar concentration (MAC) of inhalational anesthetics (5.7% desflurane, 1.97% sevoflurane and 1.1% isoflurane [9,10]) between 7:00 PM and 1:00 AM. In the day groups, experiments were performed between 7:00 AM and 1:00 PM. The research was conducted in the spring. There were six rats in each group. During the night hours the lights were not on and all of the procedures were done in the dark with red light. It has been shown that red light does not alter the circadian rhythm of rats [7].

Anesthesia apparatus, induction and maintenance Separate glass jars for every single rat were used as anesthesia apparatus. The jar volume was 450 mL. All jars had gas-in and gas-out systems. Every inhalational anesthetic was administered by its own vaporizator. Inspired oxygen and volatile agent concentrations were monitored

E. Ocmen et al. (Anesthesia Gas Monitoring 1304, Bru ¨el & Kjær Sound & Vibration Measurement A/S, Nærum, Denmark) and kept constant, and respiratory effort and skin color were also inspected during the study period. All jars were placed in a water-bath with a constant temperature of 37 C. At the end of the anesthesia blood samples were taken and rats were euthanized by decapitation. Control animals were administered isoflurane for a short time before blood samples were taken and euthanized.

Melatonin measurement In the laboratory, blood samples were centrifuged at þ 4o C (3000 g) (Hettich Zentrifugen Mikro 22 R, Tuttlingen, Germany) for 10 minutes. Plasma samples were pipetted into Eppendorff tubes and kept at e80o C until assay. Melatonin was tested with a rat melatonin radioimmunoassay (RIA) kit (Melatonin Research, RIA, Labor Diagnostica Nord GmbH, Nordhorn, Germany) using the RIA method at the laboratory of Department of Biochemistry, Faculty of Medicine, Dokuz Eylul University.

Statistical analysis Statistical analysis was performed using SPSS for Windows statistical program, version 15.0 (SPSS Inc., Chicago, IL, USA). Results were given as mean  SD. In the statistical analysis of melatonin values, Levene’s test was used for homogeneity of group variances, and the distribution was considered homogeneous with values of p > 0.05. One-way ANOVA posthoc Dunnett tests were used for comparisons between the groups. The Student t test was used to compare day and night groups. A value of p < 0.05 was considered statistically significant.

Results Forty-eight rats were included into the study and none of the animals died during the study protocol. Melatonin levels did not alter compared to the control group following sevoflurane and isoflurane anesthesia during the day hours (p Z 0.959 and p Z 0.718, respectively). The control group’s mean melatonin level was 43.17  12.95 pg/mL. Mean melatonin levels were 50.75  34.28 pg/mL after sevoflurane and 59.79  27.83 pg/mL after isoflurane anesthesia. However, after desflurane anesthesia between 7:00 AM and 1:00 PM, the mean melatonin level (212.20  49.55 pg/mL) was increased significantly compared to the control group (p < 0.001) (Figure 1). During the night hours sevoflurane, isoflurane or desflurane anesthesia did not change the melatonin levels significantly (p Z 0.904, p > 0.99 and p > 0.99, respectively). Mean melatonin values were 136.12  33.20 pg/mL, 139.84  56.29 pg/mL, 117.47  82.39 pg/mL and 128.70  44.63 pg/mL for control, isoflurane, sevoflurane and desflurane groups, respectively. Night control, isoflurane and desflurane groups’ melatonin levels were significantly higher compared with their daytime groups (p < 0.001, p Z 0.013 and p Z 0.016, respectively). We could not find a statistically significant

Please cite this article in press as: Ocmen E, et al., Effect of day/night administration of three different inhalational anesthetics on melatonin levels in rats, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.04.016

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Inhalational anesthesia and melatonin

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Figure 1. Comparison of melatonin levels after day and night time anesthesia. * p < 0.05 compared with DC. # p < 0.05 when night groups were compared with their day groups. DC Z group day control; DD Z group day desflurane; DI Z group day isoflurane; DS Z group day sevoflurane; NC Z group night control; ND Z group night desflurane; NI Z group night isoflurane; NS Z group night sevoflurane.

difference between melatonin levels of day sevoflurane and night sevoflurane groups (p Z 0.102) (Figure 1).

Discussion The findings of this study showed that while desflurane anesthesia during day hours increased the melatonin levels, night time anesthesia with any of the inhalational anesthetics used in the study (sevoflurane, isoflurane and desflurane) did not change melatonin levels. This is the first study that investigates the effect of day or night time anesthesia with the three most common inhalational anesthetics on melatonin levels in rats. Melatonin levels peak during the night, independently of sleep. Its production is inhibited by light. The sympathetic system regulates melatonin’s synthesis with b1 and a1 adrenergic receptor activation by norepinephrine [2,4]. During the night, SCN output increases norepinephrine secretion from sympathetic nerves which results in melatonin secretion from the pineal gland [11]. Melatonin is not stored in the pineal gland, after its secretion it diffuses into the blood. It can easily distribute to the tissues because it is liposoluble [2]. Therefore stressors such as surgery or pain and agents causing sympathetic nerve excitation can change melatonin levels [11]. Inhalational anesthetics, especially desflurane, are known to have sympathetic nerve excitation effects [12,13]. Arai et al demonstrated that in female patients isoflurane caused a significant increase on melatonin levels while sevoflurane caused a significant decrease during anesthesia [13]. In contrast, Fassoulaki et al could not find any significant difference in melatonin levels after sevoflurane anesthesia for dilatation and curettage, similar to the results of this study [14]. We anesthetized the rats and let them breathe spontaneously. There was no painful stimulation during the study period so we choose to administer 1 Minimum Alveolar

Concentration of each volatile anesthetic. This is compatible with the study of Kikuchi et al who investigate the relationship between circadian rhythm and anesthesia [15]. Sympathetic nerve system activation triggers melatonin secretion, therefore, an increase in melatonin levels after desflurane anesthesia can be expected. This explains our results which showed a significant increase after desflurane anesthesia during day hours. Karkela et al found a delay in the onset of nocturnal melatonin secretion with isoflurane or spinal anesthesia for minor orthopedic surgery [1]. Pang et al also showed that halothane anesthesia administered during the early dark period resulted with a phase delay in nocturnal melatonin levels [11]. We took blood samples at only one time point so we would not be able to detect a phase delay of melatonin secretion. It is believed that gamma-Aminobutyric acid (GABA), by GABAA receptors, has an important role for synchronizing SCN clock cells [2]. GABA transmits light information from SCN to the pineal gland. Kalsbeek et al demonstrated that hippocampal GABA administration inhibits the nocturnal release of melatonin [16]. It has been shown that GABAergic agents like diazepam also effect melatonin secretion [11]. Most anesthetic agents, such as inhalational anesthetics, are thought to be effective via GABA receptors. But in contrast with these reports we could not detect any significant difference in melatonin levels after night time sevoflurane, isoflurane or desflurane anesthesia compared to the control group. Melatonin is metabolized by the liver with the cytochrome P450 system [2]. Inhalational anesthetics, especially sevoflurane, are also known to be defluorinated by the liver cytochrome P450 system [17]. The different effects of these anesthetics on the P450 system and on hepatic blood flow could create the different effects on melatonin levels that we found in this study. IThe circadian clock involves different clock genes (Per1, Per2, Bmal1) at the molecular level [18]. It is known that clock

Please cite this article in press as: Ocmen E, et al., Effect of day/night administration of three different inhalational anesthetics on melatonin levels in rats, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.04.016

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4 genes such as Clock and Bmal1 control the synthesis of melatonin [4]. Clock genes such as Per1, which are expressed from the pineal gland, are regulated by norepinephrine in the same manner as melatonin [2]. Cheeseman et al showed that night time isoflurane anesthesia administered to bees has no effect on clock gene expression [19]. Kadota et al found that sevoflurane anesthesia during day hours (8:00 AMe12:00 noon) repressed mPer2 expression while anesthesia during night hours did not significantly affect its expression [20]. Likewise, Kobayashi et al also demonstrated that sevoflurane anesthesia administered in daytime hours suppressed the clock gene expression [21]. Anesthesia-related changes in clock genes’ expression could cause a phase shift of circadian rhythms such as melatonin secretion, and this could be an alternative explanation of anesthesia-induced alteration of melatonin secretion. Postoperative cognitive dysfunction is a common complication after surgery and it is related to increased mortality and morbidity. Xia et al demonstrated that cognitive function is related to circadian rhythm and melatonin treatment has positive effects on cognitive function after isoflurane anesthesia [22]. This study points out the importance of melatonin especially after anesthesia. We investigated the endogen melatonin levels after anesthesia and our findings support that melatonin secretion is disturbed by anesthesia administration. One of the limitations of this study is the time point at which we took blood samples to evaluate melatonin level. Melatonin is not stored in the pineal gland after its secretion and because of its liposolubility, melatonin blood levels are well correlated with its production rate [2]. So it is logical to detect the changes in melatonin levels at the end of the anesthesia. The major limitation of the study is that we only took one sample at the end of the anesthesia so we could not observe if these inhalational anesthetics caused a phase shift in melatonin secretion. We also could not find out when the melatonin levels turned back to normal values after anesthesia. In conclusion, desflurane anesthesia in daytime hours significantly increased melatonin levels and night time anesthesia with sevoflurane decreased melatonin levels at the end of the anesthesia at one time point. Altered melatonin rhythm following inhalational anesthesia can be related to sleep disorders and delirium observed after anesthesia. Our study showed melatonin levels after day and night time anesthesia with three commonly used volatile agents for the first time. We studied melatonin levels at only one time point, therefore further detailed experimental and clinical studies are needed to show the relationship between melatonin and anesthesia and possible mechanisms.

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Please cite this article in press as: Ocmen E, et al., Effect of day/night administration of three different inhalational anesthetics on melatonin levels in rats, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.04.016