Advanced Drug Delivery Reviews 62 (2010) 928–945

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Advanced Drug Delivery Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Disruption of the circadian system by environmental factors: Effects of hypoxia, magnetic fields and general anesthetics agents☆
Yvan Touitou a,⁎, Olivier Coste b, Garance Dispersyn c, Laure Pain c
a b c

Unité de Chronobiologie, Fondation Ophtalmologique A. de Rothschild, 29 rue Manin, 75019-Paris, France Institut de recherches biomédicale des armées, Institut de médecine navale (IRBA-IMNSSA), Toulon, France GRERCA, Inserm U666, Faculté de Médecine, 11 rue Humann, 67- Strasbourg, France

a r t i c l e

i n f o

a b s t r a c t
The biological clock of mammals is under the control of external factors, social life and the environment, and of internal genetic factors. When the biological clock of an individual is no longer in phase with its environment, either because there is no longer any harmony (desynchronization) between the two systems (shift work, night work, and transmeridian flights…) or because the perception of signals in the environment is defective (blindness) or because of a pathology, disorders of the biological clock occur resulting in persistent fatigue, sleep disorders leading to chronic insomnia and mood disturbances that can cause depression. We review here new groups of factors that have been recently studied and that can be considered as potential disruptors of the circadian time structure. These factors are hypoxia, magnetic fields and anesthetic agents whose importance has to be considered. © 2010 Elsevier B.V. All rights reserved.

Article history: Received 26 February 2010 Accepted 22 June 2010 Available online 6 July 2010 Keywords: Rhythm desynchronization Hypobaric hypoxia Electromagnetic fields General anesthetics Propofol Temperature circadian rhythm Melatonin circadian rhythm Cortisol circadian rhythm Transmeridian flight Jet lag Fatigue Circadian disruption

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Circadian synchronization and desynchronization . . . . . . . . . . 1.2. Marker rhythms of the circadian time structure . . . . . . . . . . . Magnetic fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Melatonin and the pineal gland in animal models . . . . . . . . . . 2.3. Melatonin in humans . . . . . . . . . . . . . . . . . . . . . . . 2.4. Endocrine and neuroendocrine systems . . . . . . . . . . . . . . . 2.5. Biochemical and immuno-hematological variables in humans. . . . . 2.6. Omics technologies application to EMF research . . . . . . . . . . . Altitude and hypobaric hypoxia . . . . . . . . . . . . . . . . . . . . . . 3.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Influence of hypoxia in animal models . . . . . . . . . . . . . . . 3.2.1. Tolerance and intolerance to hypoxia . . . . . . . . . . . . 3.2.2. Hypoxia effects on body temperature and locomotor activity. 3.2.3. Hypoxia effects on the SCN . . . . . . . . . . . . . . . . 3.3. Influence of hypoxia in humans. . . . . . . . . . . . . . . . . . . 3.3.1. Hypoxia effects on body temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929 929 930 931 931 931 931 932 932 932 933 933 933 933 933 933 934 934



☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Chrono-Drug-Delivery Focused on Biological Clock: Intra-and Inter-Individual Variability of Molecular Clock”. ⁎ Corresponding author. Tel.: +33 1 47 02 32 05. E-mail address: (Y. Touitou). 0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2010.06.005

. . .2. . This is named the Phase Response Curve (PRC) which corresponds to the phase shifts in the rhythm according to the time of stimulus presentation. This clock disorder leads to a desynchronization of the body because the resulting action of synchronizers on circadian rhythms to 24 h is no longer working. . such as in blindness. . . . . . . . . . . Input pathways (e. . Conclusions and perspectives . such as in experiments involving complete isolation from time references. .1. . . . . . . . . body temperature. . . . . . . . . . . and in a number of diseases involving modifications of the rhythms or the appearance of a rhythm with an abnormal period or . . . meaning the period slightly differs from 24 h (slightly longer than 24 h. . . .5. . . In this respect. . . light and social synchronizers) connect the circadian clock to the external environment while output pathways transfer circadian rhythmicity to physiologic. . . . . that is the temporal dissociation of biological clock functioning from that of the astronomical clock. . . . 3. . . . . . . . . . . . . . Circadian synchronization and desynchronization In humans. . . . . . . . . . . . in circadian disorders of the sleep–wake cycle. . . . . behavioral and biochemical parameters of the organism [2–5]. . . . . . . . . . . . . . Steroid hormones . . . . . . . It is either external when it is related to environmental factors such as jet lag [18] and shift work [19]. Background . . 4. both of which drive our biological clock but do not create rhythms. .4. we are aware of the role light plays in suppressing melatonin secretion [15]. . .Y. . the time of food intake in certain conditions etc. Touitou et al.e. The exogenous component of circadian rhythms thus plays an important part in the circadian rhythms of core body temperature. . . . . . . . . Depending upon the time a stimulus (e. . . . . . . . . . . . . a function well demonstrated in humans through sleep deprivation experiments [13]. . 4. . . Anesthetic effects on hormonal secretions . . 4.1 h to 25 h or sometimes shorter than 24 h) because the synchronizers of the environment no longer drive the period. Synchronization of biological rhythms is carried out through complex endogenous factors of genetic origin and by environmental factors or exogenous factors called synchronizers. . . . . . . .4. . . . . . . . appear to be coordinated by the SCN which is the only clock which directly receives the light-dark signal. . . . . . . . The SCN consists of a bilateral pair of small gray structures composed of about 10. . . . . . . . . . . . . Hypoxia effects on marker rhythms in long transmeridian flights . . . located in the hypothalamus above the optic chiasma at the base of the third ventricle. . . . . . or at least some of them. . . . . . . .3. .g. . .3. . . . . . . . . and ultradian if τ b 20 h). References . .3. . . . . . . . Circadian rhythms (period close to 24 h) are regulated in mammals by a main circadian clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Hypoxia effects on body temperature rhythm under constant routine conditions 3. . . . . . . . . By contrast to the preceding examples. .4. . . . . . . . . . . . . . . pulse rate and bronchial diameter because the levels of these variables or functions are increased with physical and mental activities and decreased during sleep [1]. . . . 4. . suggesting the existence of other biological clocks. . . . from 24. . . . . . . . . . . . . . . . . . Hypoxia effects on steroid hormones. . . . 4. . . . Its destruction in experimental animal models results in the disappearance of some circadian rhythms (melatonin. . . . . . . . . . . .3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . but the hierarchization of clock functions and their interdependence are still poorly understood [2]. . Anesthetics effects on clock genes . As a final result biological rhythms are of endogenous nature. sleep–wake cycle…). . Anesthetic effects on rest–activity and core body temperature cycles . . . . . . . . the main synchronizer of the clock. . . . . . . . . . . . . . . . . . . . . . . . such as during transmeridian flights (jet lag). . such as during isolation in caves or special laboratory facilities. . . . Rhythm desynchronization occurs when there is a poor detection of the synchronizers by the biological clock which is observed in several situations: when synchronizers are completely suppressed. . the two main synchronizers are the light–dark (L–D) cycle and the sleep–wake cycle. . . . . 934 934 934 935 936 937 937 938 938 939 939 939 940 941 942 1. . .g light) is applied. . . . . . . . . . . . . . . when synchronizers are altered under conditions in which the biological clock and the environment run counter to each other. . . . . . . . . . . . . though not all of them. The SCN is rhythmic in nature and the period of the rhythms generated in the SCN differs slightly from 24 h [6]. . . . 3. . . . . . . . . . When the body is no longer in phase with environmental signals. . A number of other clocks have been localized to several regions of the brain and to peripheral tissues. . . . . / Advanced Drug Delivery Reviews 62 (2010) 928–945 929 3. . . as well as the importance of light in managing the human circadian system [14]. . It receives the photoperiod signal directly from the retina by way of the retino-hypothalamic tract. . . . . . . . . . or internal such as aging [20] and certain diseases [21]. . . . . . . . .1. .2. . . . . 4. . . . . . . .1. . . . heart. . General anesthetics . . . . . that entrain rhythms to 24 h [1]. . 5. . . . . . . . . . .000 neurons. . . . . Circadian timing and duration of action of general anesthetics agents . . . . when synchronizers are no longer detected. . . . . . night work. 4. Coupling between the SCN and peripheral tissues might be achieved by nervous connections via the autonomic nervous system [4] or by humoral signals [3]. . . . . . .4. . . . . . this stimulus can cause phase advances ( i. . . . . . . . . . . .3. . . . . Certain circadian rhythms are more sensitive to exogenous factors than others. . . . . shifts of the peak time to an earlier time) or phase delays (i. . . muscle and kidneys [7–11]. . . . . . . . . individuals. organs and tissue cells. . and this is the reason that they are called “circadian” which means about a day [1]. . . . . . . . . Desynchronization is therefore the expression of changes to the subject's normal synchronization. . Similarly. . . . . . arterial blood pressure. . . . . . . . . . . . . . . Hypoxia effects on clock genes . . . . . Introduction Mammals are characterized by a temporal structure of complex biological rhythms covering a broad frequency spectrum (they are called infradian if the period τ N 28 h. .e shifts of the peak time to a later time). . .5. . . . . . . . of socioecological nature. . Melatonin . . . . . . . . . . . . . . . . . . . 3. . . . . . . . . . . . . . the circadian rhythms of plasma melatonin and cortisol are not very dependent upon exogenous factors. such as the liver. . . . . . .3. . . . the sleep– wake cycle. . .2. . . .4. . . . . . . . . . . . . . all circadian rhythms persist but free-run with respect to environmental factors. . . they are examples of rhythms with a strong endogenous component which make them major markers of the circadian synchronization of an organism [17]. . . . . . . . . . . it is important to stress the significance of sleep in the structuring of circadian rhythms [12]. . and shift work where reversing or making major changes to the timing of our social life results in a dysfunctionning of the biological clock causing bodily disorders known as shift work intolerance [22]. . . . . such as the day–night alternation. These peripheral clocks. . . . . . . . 4. . . . . the effect of the timing of meals on particular circadian patterns [16] and the relationship between growth hormone (GH) and prolactin levels and sleep [in 1]. . . . . . . . . . genetically entrained by the synchronizers of the environment. . . . Hypoxia effects on rhythm markers: core body temperature and melatonin . . . . . . . . . circadian if τ = 20–28 h . . . . . . . . . and sub-cellular organelles [1]. 1. . . . which are the object of multiple and highly complex interactions and which are present at all levels of organization: populations. . . . . . . . . . .

breast. in alcoholic patients [23. when monitored during the first hours of darkness using a dim light of 50 lx. From Selmaoui and Touitou [17]. white blood cells often used to follow the therapeutic effects of anticancer drugs.e. body temperature with its Fig. such as persistent fatigue. plasma cortisol whose circadian pattern is highly reproducible and reliable both on an individual basis and as a group phenomenon (Fig. the onset of evening rise to be defined by a marker known as Dim Light Melatonin onset (DLMO).g. 1) [17]. Circadian profiles of plasma cortisol and melatonin in young healthy men. plasma and salivary melatonin which are unaffected by masking factors (i. desynchronization becomes manifest through atypical clinical symptoms.2. Regardless of the origin. . Indeed marker rhythms can be altered in desychronized subject types as described above. 1.930 Y. The circadian rhythm of the two hormones are highly reproducible from a day to another.24] amongst others. 1. Touitou et al. It allows monitoring of the biologic timing of an organism and/or the timing of a related rhythm showing a fixed time relation to the rhythm used as marker rhythm and provides information on the synchronization of indivi- duals which is important for decisions about the timing of both treatment and diagnosis e. / Advanced Drug Delivery Reviews 62 (2010) 928–945 phase not found in healthy subjects such as depressive states. exogenous environmental factors masking the actual endogenous rhythms) other than bright light and which allow. A marker rhythm is a physiological variable with a prominent circadian rhythm such as body temperature. ovarian and prostate cancers [21]. Both are useful circadian markers of the time structure. Marker rhythms of the circadian time structure A marker rhythm is a rhythmic variable characterizing the timing of the endogenous rhythmic time structure.e. sleep disorders leading to chronic insomnia. and mood disorders that can cause depression and poor appetite [22]. diseases and preventive healthcare [25]. hormonedependent cancers i.

The major sources of Extremely Low Frequency Fields (ELF) generation are electrical appliances.g. the oncostatic properties of melatonin have been described [35–37] as has its association with some depressive disorders [38. This lack of an effect of acute exposure on Fig. though most often more than one marker rhythms is used to assess the rhythm synchronization of subjects under study.39] and with disorders of the circadian rhythm shown to generate neurobehavioral disturbances [40].05) with control group (Ctrl). sleep and mood disorders. They found that a single 12 h exposure resulted in a significant 30% decrease in melatonin levels and a 23% decline in pineal N-acetyltransferase activity (NAT). The secretion of melatonin is known to be inhibited by light [15] which is the visible part of the EMF. assessing therapeutic responses.Y. thus suggesting that magnetic fields may have a cumulative effect upon pineal function [47]. This study showed that the sensitivity threshold varies with the duration of exposure. the hypothesis was put forward that a decrease in the secretion of melatonin by the pineal gland might promote the development of breast cancer in humans [35].3. there is little experimental or epidemiological basis for considering electric fields to be harmful for human health [34].g white blood cells in cancer research. 2. Magnetic fields might also change either the electrical activity of the pinealocytes or their ability to produce melatonin or both. Moreover. 60 Hz in America) [41]. Due to the ubiquity of electrical appliances and apparatus in modern society. No clear explanation exists for these various and contradictory results. 2) [47]. only with the highest intensity used (100 μT). the key enzyme for melatonin synthesis. Exposure to EMF has also been shown to result in a reduction in pineal and plasma melatonin in various species and under photoperiodic conditions [42–46]. Only 10 and 100 μT were able to depress serum melatonin and pineal activity. both 10 μT and 100 μT intensities resulted in a significant 42% decrease in plasma melatonin levels.1. Effects of chronic exposure of male rats to a sinusoidal 50-Hz magnetic field ( from 1 to 100 μT) on nocturnal pineal activity. within a species.2.31] although this soon gave rise to controversy [32.g. Melatonin and the pineal gland in animal models As early as 1963. animals and humans live in an extremely complex electric and magnetic field environment. Melatonin in humans Research on the possible effects of magnetic fields in humans is important from a public health perspective since it is known that alterations in melatonin secretion (e. time of sampling. 2. Background The debate over the connection between electromagnetic fields (EMF) and cancer has become a hot issue in industrialized countries over the past years. core body temperature in sports research. Selmaoui and Touitou [47] submitted rats to a 50 Hz sinusoidal magnetic field during the night at different intensities for 12 h (from 14:00 h to 02:00 h) or repeatedly 18 h (from 14:00 h to 08:00 h) per day for 30 days. high power transmission and distribution lines. The choice of a marker rhythm depends upon the aims of the research e. The characteristics of the magnetic field (linear or circular polarization). and altered vigilance. Magnetic fields 2. Moreover. timing of therapy. 2. The rats were exposed every day from 14:00 to 08:00 h for 30 days at three different intensities. No effect was observed on HIOMT activity. reduced amplitude or phase shift) are associated with clinical disorders such as fatigue. This resulted in the “melatonin hypothesis” as a tentative explanation for the occurrence of clinical disorders possibly related to exposure to EMF (50 Hz in Europe. A marker rhythm is useful in the assessment of the rhythm synchronization of an organism and can be used as a tool in various circumstances for decision making e. In this context the International Agency for Research on Cancer (IARC) classified ELF electric fields in category 3 which in the classification corresponds to «inadequate evidence» of deleterious effects and placed ELF magnetic fields in category 2B. The 30 days repeated exposure showed that while the 1 μT intensity had no effects on pineal function. the animal species and. corresponding to the category of agents that are «possibly carcinogenic». / Advanced Drug Delivery Reviews 62 (2010) 928–945 931 peak in the afternoon and a trough about 3 h before sleep onset. We did not find any effect on melatonin levels with short exposure of young healthy volunteers during night (9 h exposure) to a 50-Hz (10 μT) magnetic field [48]. In contrast to magnetic fields. . NAT activity was also decreased (Fig. and ambulatory activity monitored using an actometer worn on the wrist. A possible change in the spatial structure of the photoreceptor pigment rhodopsin due to the electric field induced by the magnetic field has been proposed. The asterisks indicate a significant difference (p b 0. 2. some in vivo studies suggest that magnetic fields may induce biological effects in organisms that could have deleterious consequences. melatonin and cortisol in research dealing with shift work. From Selmaoui and Touitou [47]. It has to be noted that these extremely low frequency electric and magnetic fields are separate entities.33]. Increasing concern in recent years about the effects of human exposure to electromagnetic fields (EMF) has been stimulated by a number of epidemiological studies reporting a possible link between magnetic fields and human diseases including leukemia [26–29] and depression [30. the strain have a role in determining the biologic response obtained. The spectral sensitivity of the circadian system peaks between 450 and 480 nm. In order to compare short-term and long-term exposure effects. Touitou et al. all of which are clinical signs of a desynchronization of circadian rhythms.

This study was carried out in 15 healthy chronically (in the workplace and at home) exposed men (daily and for 1 to 20 years) to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. nerves and bacteria which makes it difficult to compare data from different research papers on this topic and to arrive at definite conclusions on the potential effects of EMF on biological systems [75]. The measurement of biogenic amines and their metabolites in blood and urine has become firmly established as a diagnostic indicator for some types of cancer. Similarly. None of these amines was affected by exposure to magnetic fields [74]. 2. Likewise. 2. platelets. lipids.4. the circadian profiles of Thyroxine Binding Protein (TBG) and TBK which represents TBG capacity in exposed subjects did not differ from those of the sham-exposed: both peaked during the day and reached their lowest levels during the dark phase. 3.We also documented under the same conditions and on the same subjects hematologic and immunologic functions (hemoglobin. As shown here the exposed subjects experienced no change in the hormone levels or circadian profile of melatonin. We therefore examined the effects of electromagnetic fields on the adrenocortical system and the hypothalamo-pituitary-thyroid (HPT) axis. Fig. CD8. 3. monocytes. [52]. In rats. and 5-hydroxyindoleacetic acid). including phaechromocytoma. tissue cells. We found that the circadian rhythm of the HPT and hypothalamo-pituitary-adrenal axis (HPA) functions was not affected by acute exposure (9 h) to either a continuous or an intermittent 50-Hz magnetic field [66]. These results are consistent with those of animal experiments that have not found any clear effect of electric fields on the hypothalamic–pituitary–thyroid and adrenal axes [67–69]. 3) [52]. leukocytes. neuroblastoma and related neurogenic tumors. The consequences on long-term exposure are not well known in humans.g. neither on their circadian pattern nor on their plasma levels [70].932 Y. The results we obtained do not indicate that the magnetic fields had any effect on these variables [71]. . These data. melatonin administered late in the afternoon for 10 days inhibits thyroid growth in mice and rats [59]. noradrenaline. We evaluated the nocturnal levels of urinary biogenic amines (adrenaline. From Touitou et al. Endocrine and neuroendocrine systems A relationship between the pineal gland and the adrenal gland has been documented in vitro [54] as has the relationship between the pineal and other glands of the endocrine axis. CD4. The difference in the effects observed in animals and humans might be related to differences in the anatomical configuration of the pineal gland and the nocturnal rhythm of rodent activity [52]. red blood cells. B) in the first-void morning urine (20:00 to 08:00).4-dihydroxyphenylacetic acid. exposure up to 120 days did not affect the hematological variables [72. 2. / Advanced Drug Delivery Reviews 62 (2010) 928–945 melatonin secretion has also been reported by several authors [49– 51]. thyroid. depending on the time of day a single dose of melatonin administered to pinealectomized rats markedly affects their nocturnal thyroid activity [58].6. blood cells/vessels. and lymphocytes subpopulations) (CD3. Comparative nocturnal plasma melatonin profiles (A) and 6-sulfatoxymelatonin concentration ( 6SM. We therefore conducted a study on workers exposed on a daily basis to magnetic fields both at work and at home (EDF electrical workers) for 1 to 20 years and we showed that this exposure did not lead to alterations in their melatonin secretion (Fig. We found no effect of magnetic fields whatever the condition of exposure on any of the studied variables. We will give here some recently published examples of difficulties in comparing EMF exposure to such heterogeneous biological materials. however. nitrogen substances.g. 15 healthy unexposed men served as controls. dihydroxyphenylalanine. enzymes. Considering this hypothesis in light of findings that exposure to electromagnetic fields appears to attenuate the nocturnal melatonin increase in experimental animals [47. Touitou et al. Different sensitivity to magnetic fields between species can also play a role in these differences as it is known that some species perceive magnetic fields differently [53] and it is possible that some subjects are more sensitive to magnetic fields than others. hematocrit. homovanillic acid. e. electrolytes. dopamine. Omics technologies application to EMF research The application of high-throughput omics technologies to investigate the influences of EMF on biological systems has been recently reviewed in a paper underlining the heterogeneity among the biological materials investigated e. All of the clinical signs reported in some studies of people living near electric lines or substations thus do not appear to be associated with an alteration in their melatonin levels.63–65]. 10 μT) on the circadian rhythm of biochemical variables in an exhaustive study concerning proteins.73]. do not rule out a possible effect with chronic exposure. Biochemical and immuno-hematological variables in humans We evaluated in young healthy healthy subjects the effects of nocturnal acute exposure to both continuous and intermittent magnetic fields (50-Hz. These and other similar results [60–62] suggest that the pineal gland may be related to thyroid activities. NK cells and B cells). we wondered whether and in what ways electromagnetic field exposure might affect the endocrine and neuroendocrine systems. they are also considered to be markers of stress.5. pituitary and gonads [55–57]. In fact.

2. whereas no phase shift was reported in animal submitted to continuous severe hypoxia. The survival time was indeed longer during the light period than during the dark period under constant hypoxia. which is not yet the case [75]. The amplitudes and 24-h mean levels of the circadian rest–activity and energetic metabolism rhythms were dramatically decreased. the active phase for the animals) with high levels of internal temperature and glycemia. when the mice were fed ad libitum.1.e. which lead to free-running conditions for the circadian system. by exposing cells of the breast cancer line MCF-7 to EMF it has been found that EMF alter the expression of estrogen receptor cofactors. during the light phase. has been found to be unaffected by exposure to 50-Hz EMF [76].500 m simulated altitude were reported [82]. The authors concluded that severe intermittent hypoxia may lead to a phase delay of circadian rest–activity rhythm in free-running conditions. Most breast tumors become resistant to tamoxifen and it has been shown that EMF reduce the efficacy of tamoxifen in a manner similar to tamoxifen resistance. 3. Proteomic methods used to investigate the effect of EMF exposure on SF767 human glioma cells revealed significant alterations in the sot density of a subset of treated cells [79]. The authors showed that a brief exposure to normobaric hypoxia obtained by a decrease in the inspired oxygen fraction (FIO2 = 10 % for 15 min twice a day at 07:30 and 19:30 h) led to a disappearance of the nocturnal acrophase and a decrease in 24-h mean levels of ventilation (Ve) and aerobic metabolism (VO2). the circadian temperature rhythm also disappeared during similar hypoxic exposure and then reappeared without any apparent phase shift. The study showed there was circadian rhythm in the cerebral resistance to hypoxia. 4 h after light onset. Body temperature and locomotor activity were found to be differently affected.4 min in their locomotor activity rhythm.83] suggest there is a phase opposition between hypoxic resistance rhythms on the one hand and core body temperature and blood glucose rhythms on the other hand. / Advanced Drug Delivery Reviews 62 (2010) 928–945 933 The expression of α3. corresponding to a rest phase) than at 16 HALO (i. independently of the circadian clock. Thus it is clear that direct comparisons of data from studies using different products are difficult. a major component of the nicotinic cholinergic system implicated in various neurological disorders.e.2. Subsequently. replication and control experiments with alternative technologies are needed. In addition. Hypoxia effects on body temperature and locomotor activity In synchronized (L/D cycle = 12:12) adult rats submitted to a 5-day severe hypoxia (FIO2 = 10.e. Altitude and hypobaric hypoxia 3. 3. whereas the inspired O2 fraction remains unchanged. classically located in the suprachiasmatic nuclei.2. arterial and tissue compartments and finally determines a hypobaric hypoxia. Several factors may explain this difference: a continuous vs. intermittent hypoxic exposure.1. 3. The decrease in PB in turn leads to a decrease in O2 partial pressure in alveolar. Resistance to chronic hypoxia is high during the light phase (i. the activity level almost abolished at the beginning of the exposure progressively increased. All these results [82. On the contrary. Placed in these conditions. Background A peripheral deficit in oxygen (O2) delivery is called hypoxia. using the same endpoints and in different laboratories. studies dealing with the influence of hypoxia on the circadian time structure including clock genes are rather few in both animals and humans. This rhythm was completely reversed by restriction of food presentation from 09:00 h to 15:00 h. This problem is crucial in mountaineering activities and also in aeronautics to protect subjects against the deleterious effects of acute hypoxia.3. A negative correlation found between the survival times and the levels of core body temperature and of glycemia suggested once again that the rhythm of hypoxic tolerance was closely linked to the circadian rhythms of temperature and blood glucose in mice. The expression of PHOX2A. These data were corroborated in mice [83]. A decrease in locomotor activity without alteration of the total duration of the active span in the golden hamster has been found when placed in constant darkness (D/D) and submitted to repeated severe hypoxic 3-h episodes (FIO2 = 8 %) for seven consecutive days at mid-subjective day for the animals (circadian time CT = 06:00-09:00) [88]. Although the physiological consequences of hypobaric hypoxia have been extensively studied in the last past century. α5 and α7 nicotinic receptor sub-unit genes in the SH-SY5Y neuroblastoma cell. Touitou et al. In constant lightening conditions (L/L). a masking effect which may act differently according to photoperiodic conditions of synchronization. by a severe 63-h hypoxic exposure (F I O 2 = 10 %) in adult rats synchronized by L/D = 12:12 photoperiodic conditions [87]. Altitude is one of the main environmental causes of hypoxia in healthy subjects. A more recent study deals with the effect of acute hypoxia on ventilation and metabolism in newborn rats [84]. which for the authors may contribute to the induction of tamoxifen resistance in vivo [80]. which can be shifted by the time of food presentation. i.2. Circadian variations of tissue concentrations of the vasoactive intestinal peptide (VIP). but stayed at a lower level compared to the reference level [87]. were abolished in the SCN as were pineal 5-HIAA and serotonin which plays . All these results suggest that hypoxia had central effects more on hypothalamic thermic centres than on the circadian masterclock. the rest phase for the animals) with low levels of internal temperature and glycemia. This deficit may be related to different causes. Tolerance and intolerance to hypoxia The existence of a circadian and circannual rhythm of tolerance to hypoxia in mice submitted to brief (20 min) and repeated episodes of severe hypoxia (FIO2 = 5%) in mice was suggested as early as 1978 [81]. These differences were interpreted as a result of circadian variations in the capacity to mobilize and use carbohydrates reserves. 3. 4 h after the beginning of the dark phase corresponding to an active phase). Core body temperature rhythm reappeared by returning to normoxia without any phase shift. The depression of circadian oscillations persisted with a bilateral sino-aortic denervation of the rats and was therefore considered independent of peripheral chemosensitivity [86].Y. resistance to chronic hypoxia is low during the dark phase (i. Survival time was twice longer in rats exposed to severe hypoxia at 4 HALO (i. Whereas body temperature presented several hypo and hyperthermic components.2. the hamsters presented a cumulative phase delay of 46. differences in hypoxic tolerance according to the time of the day in rats synchronized by Light/Dark (L/D) cycle = 12:12 and submitted to a 10.5%).e. a real phase delay which may be too small for being detected according to the sensitivity of the measures. Altitude leads to a decrease in barometric pressure (PB) with a negative exponential relation. Influence of hypoxia in animal models 3.e. which plays a role in the output of the biological clock. a disappearance of the circadian rhythm of temperature was observed [85]. The transcriptional response of human umbilical vein endothelial cells to various patterns and intensities of 50-Hz EMF failed to produce regulated candidate genes [78]. Hypoxia effects on the SCN Using a severe and longer duration (14 days) of continuous hypoxia (FIO2 = 10%) in rats alterations of the circadian rhythmicities of neurotransmitters in the SCN and the pineal gland [89]. and/or the statistical power of the experiment. PHOX2B and of their target gene dopamine-βhydroxylase was not modified by EMF in a human neuroblastoma cell line SH-SY5Y [77].

2. except for an increase in the 24-h mean level [95]. By contrast. Finally. In our laboratory. under constant dim light conditions of 200 lx) in a climatic room (25 °C) [94]. Black arrow indicate day of exposure. the authors conclude that the circadian alterations observed in humans may contribute to sleep disturbances observed by sleeping in altitude [94]. the cycle of cortisol was established with only four measures per day which does not allow precise detection of phase changes. 3.e. and cognitive tasks rhythms in 3 pilots [92]. Acute hypoxia exposure as phase shift inducer (mean times of acrophase occurrence ± SD). the circadian pattern was unaltered in subjects presenting a high resistance to hypoxia.e. Touitou et al. Hypoxia effects on body temperature Few studies deal with the effects of hypoxia on human circadian time structure. snacks every 2 h. 4).3. local vasodilatation leading to an increased blow flow) which may play a role in modulating the circadian rhythms as observed under hypobaric hypoxia at high altitude. the nitric oxide (NO) level generated by neuronal NO synthase (nNOS) increased in the SCN and may involve local hemodynamic changes (i. / Advanced Drug Delivery Reviews 62 (2010) 928–945 a key role in the synchronization of biological clock via nocturnal melatonin secretion. Historically. [92]. These studies on animal model showed that continuous hypoxia alters the circadian profiles of core body temperature and locomotor activity. with the appearance of ultradian components [93]. From Ashkenazi et al. 8000 ft (~2400 m) and 12.3. some weeks later in the middle of the polar winter (i. Normoxic exposure (FIO2 = 21%) as the standard was followed by hypoxic exposure (FIO2 = 13% obtained by adjunction of nitrogen in the climatic room. Ashkenazi et al. These delays persisted for 4 days after exposure (Fig. 3. we recently showed that plasma cortisol 24-h cycles were altered by diurnal 8-h exposure to mild hypobaric exposure. By contrast. Besides. 3. whereas the phase and the 24-h mean levels remained unchanged (Fig. Moreover.3.000 ft (~7600 m)) induced a phase delay of oral temperature. 5). This circadian effect of hypoxia may be unmasked in these experimental conditions by comparison with a continuous exposure. . 3. Interindividual differences were found. corresponding to maximal cabin altitudes for pressurized large cabins fixed by aeronautical regulations in civil and military aviation respectively. during an expedition to Antarctica's mountains. These alterations of the expression of circadian rhythms may be the impact of hypoxia on the SCN. body temperature.3. using a constant routine protocol (total sleep deprivation in a standardized semi-recumbent posture. then by normoxic exposure for recovery evaluation (total of 3 experimental 28-h sessions). Nevertheless.e. all subjects presented alterations in their rhythms. Influence of hypoxia in humans 3.4. simulating the conditions during a prolonged flight in a pressurized cabin [96]. hand grip. However. Daily shifts were observed in the hour of highest level of some physiological parameters on the left part and of the time needed to accomplish some cognitive tasks on the right part.000 ft (~3600 m). testosterone and gonadotrophin patterns were not significantly altered in the same acute experimental conditions [97]. plasma melatonin. 4. corresponding to an equivalent altitude of 3600 m). An initial drop in plasma cortisol was observed under hypobaric hypoxia with a rebound of secretion just after the hypoxic exposure. Hypoxia effects on rhythm markers: core body temperature and melatonin We documented the effects of diurnal 8-h hypobaric exposure on circadian markers (body temperature. the effects of continuous hypoxia were examined during a controlled laboratory longitudinal study.3. Phase shifts are not constantly observed though discrete phase delays have been reported for intermittent hypoxic exposure. in 1982 showed that a brief acute hypobaric hypoxia (2-3 min at the simulated altitude of 25. The circadian phase and amplitude of the studied rhythms were altered in subjects presenting a low resistance to hypoxia at the 30th day of the expedition with appearance of an ultradian component around 12 o'clock. considered as the main circadian clock. salivary sodium and potassium) of human circadian rhythms in response to changes in the photoperiod [93]. and urine 6sulfatoxymelatonin) and on sleep through studies at two simulated altitudes i. with decreased 24-h mean levels and amplitudes [review in 91].1. A marked decrease of the circadian amplitude of core body temperature rhythm and a profound alteration of the circadian rhythm of O2 consumption were observed whereas heart rate and arterial blood pressure rhythms remained unchanged. during the polar night equivalent to constant darkness conditions). a prolonged 8000-m exposure in a hypobaric chamber increased the expression of c-Fos (used as marker of neuronal activation) in the SCN of male adult Wistar rats [90]. in the adaptation ability of some variables (heart rate. These results are concordant with studies on rodents reported above [86]. Indeed. Hypoxia effects on body temperature rhythm under constant routine conditions Hypobaric hypoxic exposure might not be the unique factor involved in the circadian alterations observed in the two last studies performed in ecological conditions. Hypoxia effects on steroid hormones The plasma cortisol circadian profile was not modified in the course of 79-h exposure at an altitude of 4350 m in a group of climbers.3. Fig.934 Y.

[92]. independently of the jet lag phenomenon related to quick crossing of several time zones during a transmeridian flight [102]. suggesting a physiological effect of hypoxia on body temperature or a possible phase shift of temperature rhythm. By contrast. acting on the circadian time structure. are impacted by hypoxic exposure [88. Hypoxia effects on marker rhythms in long transmeridian flights As described above.100]. Cabin altitudes of civil large aircrafts usually reach 5000 to 6.89] and very recent genetic studies on clock genes contribute to providing novel clues concerning the role of hypoxia in the circadian system. Moreover. 9).000 ft in the ancient planes. and plasma melatonin) were studied in aeronautical settings [98–102]. [98].000 ft exposure (Fig. From Coste et al. From Coste et al. We therefore concluded that prolonged mild hypoxia. 6. All these results strongly suggest that such exposure leads to a real phase delay of about 1 h. In parallel. Fig.5. main actors of the circadian system. 8) [99] followed by a significant decrease in nocturnal urine 6-sulfatoxymelatonin values during recovery (Fig. Alterations of cortisol secretion circadian patterns during altitude exposure. 3. The alterations were particularly marked in the youngest subjects and were once again compatible with a phase delay of melatonin in response to hypoxic exposure [99. 6) [98]. 5. In a second experiment.100].000 ft exposure. 7) [98. military large aircrafts are still less pressurized. a decrease in the nocturnal peak of plasma melatonin was initially described (Fig. Touitou et al. A delay in the evening decline of body temperature was initially observed mainly during the 12.Y. this delay persisted also during recovery.3. with a moderate but significant impact on recovery sleep. whereas the phase and the 24-h mean level remained unchanged. Effects of an 8-h diurnal exposure to mild hypoxia on core body temperature circadian patterns. A delay in the evening decline of core body temperature was initially observed mainly during the 12. Some data in rodents indicates that the functioning of the SCN and the pineal gland. An initial fall of plasma cortisol was observed under hypobaric hypoxia with a rebound of secretion just after the hypoxic proof. G and M and CD4 CD8 lymphocytes counts) were detected in the same experimental conditions [101]. no significant alterations of immune circadian profiles (immunoglobulins A. / Advanced Drug Delivery Reviews 62 (2010) 928–945 935 Fig. suggesting a real phase delay and not only a transient physiological effect of hypoxia on body temperature (Fig. may contribute to post-flight fatigue. plasma cortisol. . and nearly 8000 ft in recent ones. the effects of mild hypobaric hypoxia on circadian markers (core body temperature.

the effects of mild hypobaric hypoxia may have been different with other clock time exposures. Effects of an 8-h diurnal exposure to mild hypoxia on core body temperature circadian patterns during recovery. Hypoxia effects on clock genes In the nineties. growth cell. Touitou et al. apoptosis. it has been shown that exposure to hypoxia leads to increased PER1 and CLOCK protein levels in the mouse brain [116]. a so-called “Clock gene” was described in the mouse suprachiasmatic nuclei [111. 7. including cell differentiation. and occasionally digestive signs. whereas basic helix–loop–helix transcription factors BHLHB2 (also referred as DEC1/Eip1/SHARP-2/Stra13/Clast5) and BHLHB3 (also referred as DEC2/SHARP-1/SHARP1) are regulated by many extracellular stimuli. and particularly by hypoxia [114]. Based on co-immunoprecipitation experiments showing a protein-protein interaction between PER1 and α sub-unit of HIF-1. / Advanced Drug Delivery Reviews 62 (2010) 928–945 Fig. mostly commonly fatigue. hypobaric hypoxia may be especially important. This gene encoded a protein containing basic helix–loop–helix (BHLH) and PAS (PER– ARNT–SIM) domains [113]. Moreover. it has been suggested that hypoxic effects observed on clock genes may be . The PAS domain is an important structural feature for the genes involved in circadian rhythmicity. BHLHB2 and BHLH3 are known to play pivotal roles in multiple signalling pathways. suggesting a rich array of potential interactions relevant to the regulation of the suprachiasmatic circadian clock [112]. immune system. and in this regard no differences have been found between transmeridian and north–south flights [106–110]. Multiple members of the basic helix-loop-helix/PAS including clock genes and hypoxic-inducible factor-1 alpha (hif-1α) family were found to be expressed in the suprachiasmatic nuclei. associated with a decrease in cognitive performance. sleep and mood disorders. Indeed. 3. oncogenesis. From Coste et al. Long transmeridian flights provoke clinical complaints in passengers and crewmembers. Moreover. Moreover. like with a night exposure for example.936 Y. Most studies dealing with the biological attributes of jet lag and circadian time structure in humans do not take into account any other flight factors [104. These symptoms are related to the desynchronization of the body's circadian rhythms and make up a symptom complex referred to as jet lag [review in 103].105]. [98]. Environmental cabin factors may therefore be involved and contribute to post-flight fatigue by altering circadian patterns independently of the number of time zones crossed. regardless of whether time zones are crossed. circadian rhythms and sleep homeostasis. the Fu group recently published results dealing with a specific mutation of DEC2 linked with the very short-sleeper phenotype [115]. Of these factors. Delayed evening decline of body temperature and delayed shift of thermal trough observed during both altitude exposure and during recovery suggested a real phase delay of body temperature rhythm.4. has been described after long flights.112]. post-flight fatigue in pilots.

as recently described [98–100]. an increase in interleukin-6 (IL-6) [119]. 4. This effect is associated with a loss of circadian expression of the clock genes Rev-erb α and Bmal1 and the clock-controlled Dbp because STRA 13 and DEC2 proteins both antagonize CLOCK: BMAL1 dependent transactivation of the Rev-erb α and Dbp promoters. and desflurane). Touitou et al. hypoxia has not only physiologic effects but also a circadian effect. ketamine. In the days following general anesthesia. Two kinds of general anesthetics are commonly used in human surgery practice: intravenous agents (propofol. / Advanced Drug Delivery Reviews 62 (2010) 928–945 937 Fig. modulated by HIF-1α [116]. Hypoxic fibroblasts showed an alteration of Stra13 and Dec2 circadian gene expression. A real cross-talk seems to exist between hypoxic and circadian pathways with a cooperative role for HIF-1 α and CLOCK proteins in transcriptional activation of target genes like the vasopressin gene [117]. especially in the younger subjects. General anesthesia can be described as a pharmacologic state involving amnesia. This latter effect may also depend on the clock time of exposure. halothane. Thus. Decrease of plasma melatonin nocturnal peak at both studied altitudes was observed. the fact that DEC2 is also involved in sleep length control in mammals may explain that hypoxia may have some consequences on recovery sleep after hypoxic exposure via a circadian effect. immobility. General anesthetics 4. Moreover.1. patients . Finally. like that occurring in sleep apnea syndromes may alter clock gene expression via an inflammatory mechanism. as many other synchronizers also called Zeitgebers. 8. From Coste et al.Y. unconsciousness. and analgesia with the aim of creating a state of sensory deprivation to induce a lack of motor reaction to stimuli and to obtain explicit amnesia [121]. etomidate. Effects of an 8-h diurnal exposure to mild hypoxia on plasma melatonin circadian patterns.e. Background Clinical research on circadian rhythms in patients after their surgery suggests that both general anesthetics and surgery can alter the circadian time structure since patients complain of fatigue and sleep disorders suggestive of a disturbance of the circadian rest–activity cycle [120]. which impact the expression of circadian clock genes. and thiopental) and inhaled gases (sevoflurane. [99]. two circadian transcriptional regulators that are overexpressed and no longer rhythmic in hypoxic fibroblasts [118]. isoflurane. i. All these studies suggest that hypoxia may act on specific transcriptors. an intermittent hypoxia.

it is . Zeitgeber is a chronobiologic term which can be define as follows: under standard light–dark cycles (12 h of light/12 h of darkness). Whatever the endogenous origin of this day–night difference in the effects of anesthetics. From Coste et al. 9. Circadian timing and duration of action of general anesthetics agents It is well-established in rodents and rabbits that the efficacy of anesthesia was better and/or the duration longer with anesthetic administration during the rest span compared to activity span for pentobarbital [123]. ZT16 (4 h after the beginning of activity period). We found that on the day after anesthesia. and loss of vigilance. A significant decrease of nocturnal excretion of 6-sulfatoxymelatonin occurred only in the 22–28 year group whereas the excretion remained stable in the 29–38 year group. In addition. the amplitudes of both rest–activity and body temperature rhythms were decreased on the first and second days after anesthesia. Variations in the duration of action of general anesthetics could also be related to circadian variations in the post-synaptic GABA receptors. [100]. The urinary excretion of 6-SM was expressed as a ratio of the urinary excretion of creatinine (μg of 6-SM/mmol of creatinin). The disruptive effects of general anesthesia on circadian time structure might have considerable consequences in humans and sustain post-operative wake–sleep disorders. Since anesthesia is not uncoupled from surgery.000 ft). These results were obtained 4. ketamine [124] and more recently for propofol [122. peak activity and maximal receptor-binding affinity of which occurs during the rest span [128. propofol induced a significant 60. often complain of sleep and mood disorders.2.3. the time of lights “on” defines Zeitgeber time zero (ZT 0) and the time of lights “off” defines Zeitgeber time twelve (ZT 12).938 Y. Anesthetic effects on rest–activity and core body temperature cycles It was first shown in rats studied in constant darkness( which is a condition reflecting the endogenous component of the clock) and anesthetized near the rest–activity transition point with propofol that the drug induced a 1-h phase advance of the rest– activity rhythm in these specific laboratory conditions [125]. Urinary patterns of 6-sulfatoxymelatonin (6-SM) of healthy subjects of two age groups during three consecutive 24 h cycles D0 (reference). This day–night difference in the effect seems to be independent of liver cytochrome P-450 content and activity [126] which may suggest that these differences in drug-effects are related to circadian differences in the sensitivity of the central nervous system. 4. D1 (diurnal hypoxic 8-h exposure from 08:00 to 16:00 h). it is difficult to dissociate the proper effects on the circadian time structure of general anesthetics from those of surgery which include amongst others pain.125]. important to take it in account in any the research dealing with the effects of general anesthetics on biological rhythms. Touitou et al. surgical stress and immobilization in bed. tissue 80-min phase advance of both rest–activity and body temperature rhythms and that this shift persisted the second day after anesthesia [130]. Propofol was administered at three different Zeitgeber times: ZT6 (middle of the rest period). / Advanced Drug Delivery Reviews 62 (2010) 928–945 Fig. and D2 (recovery) under two experimental conditions (8000 ft and 12. We thus found it worthwhile to examine whether general anesthesia with propofol can impact the rat circadian temporal structure by disturbing circadian rest–activity and body temperature rhythms under normal light–dark conditions closer to light/dark conditions in humans (light–dark 12:12 h).129] . ZT10 (2 h before the beginning of activity period). though circadian rhythms in liver enzymes involved in drug metabolism may also play a role [127].

amongst other factors. We showed that diurnal rest was increased on the day of anesthesia and the following 24 h whereas nocturnal sleep was unchanged [130]. and noon. In recent studies by our laboratory on the effects of propofol on the circadian time structure in humans. the phase shift induced by propofol at ZT6 and ZT16 is around 60 min whereas it is around 80 min when propofol is administered at ZT10.4.138].) decreases the temperature circadian amplitude on the day of anesthesia without any phase-shift [136]. For the in vivo experiments. that isoflurane (at subanesthetic dose given between 9:30 and 10:30 a. in healthy human volunteers. a medical act without surgical intervention. drug administration before surgery and the age of patients. These contradictory data may be explained by differences in patients' recruitment. anesthesia was performed in the morning. ..m. Melatonin General anesthesia and surgery are associated with sleep disorders during the post-operative period. Indeed. ZT10 and ZT16) induces a dramatic increase in corticosterone secretion during the early recovery period without effect on ACTH secretion which excludes a primary stress-like activation of the hypothalamo-pituitary-adrenal axis [133] (Fig. propofol (administration time not precised) was shown to increase the secretion of corticosterone (the main glucocorticoid in rodents). Changes in the interdaily stability (IS) and intradaily variability (IV) parameters (expressed as arbitrary units (mean value ± SD)) for the 72 h period following propofol. general propofol anesthesia impacts the circadian time structure and particularly the rest–activity cycle in rats [130]. These observed effects could be due in fact to a residual decrease activity induced by anesthesia in the following hours and a subsequent decrease in the heat production. the effects are more important at ZT10 than at ZT6 and ZT16.) may also be involved in these differences. Ketamine anesthesia during the rest period (ZT3/ZT4) has also been shown to perturb the circadian rhythms of both body temperature and general locomotor activity on the day of anesthesia but with a return to basal values on the day after anesthesia [131]. 10). The inhibitory effects of propofol on adrenal steroidogenesis have been evidenced in vitro during the first step of steroid synthesis [143] between cholesterol and pregnenolone. and went back home some hours after anesthesia. 12) [134]. / Advanced Drug Delivery Reviews 62 (2010) 928–945 939 whatever the time of administration of propofol. Different and contradictory data have been described with two other anesthetics. However. 10. a glucocorticoid hormone synthesized by the adrenal cortex exhibiting marked circadian variations [137. are decreased during the time of a surgery (in the morning) using propofol as an anesthetic [120]. GABA seems to be involved in transmitted signals from the SCN to the paraventricular nucleus stimulation of melatonin synthesis Fig.4. ketamine and thiopental. Steroid hormones In humans. rats were exposed to L/D 12:12 conditions and anesthetized with propofol around their peak of melatonin secretion (Zeitgeber Time16) and trunk blood samples were collected according to 7 Zeitgeber Times to assess propofol effects on circadian melatonin secretion. we aimed at looking for the effects of this anesthetic on patients. We showed that in vivo propofol disrupts melatonin by significantly decreasing its secretion (22–28%) immediately after the wake up from anesthesia and then increasing significantly melatonin secretion 20 h after anesthesia (38%) (Fig. With regard to laboratory animals. Since propofol is one of the most commonly used anesthetics. From Dispersyn et al. Our patients received short-duration general anesthesia with propofol for ambulatory colonoscopy. In our study and in the literature. Contradictory data have been published on the effects of sevoflurane on cortisol secretion after operation which was found to be either increased for up to 12 h after surgery [139] or decreased 2 to 4 h after surgery [140]. this does not allow the actual effects of general anesthesia to be separated from the surgical act itself. The propofol anesthesia for colonoscopy was performed between 8 a. Touitou et al. timing of anesthesia and surgery. We also showed. Among the few studies focusing on the effects of general anesthesia on rest–activity and body temperature rhythms. The type of surgery (cataract. haemorrhoidectomy. [132].Y. Propofol acts via a positive modulation of the inhibitory function of the neurotransmitter Gamma-aminobutyric acid (GABA) through type-A GABA receptors which are expressed in many brain areas. i. including the outputs from SCN [146]. soon (5 min) after the injection with a parallel increase in B-endorphins which suggested that propofol stimulates the release of both CRF and ACTH resulting in an increased corticosterone secretion [141]. using non-parametric analysis. We demonstrated here that synchronization to local time is impaired for some days by light anesthesia with propofol. The results suggest that this increase may be due to a shift in the circadian rhythm of melatonin which is coherent with our data of a phase advance of the rest-activity and temperature rhythms in rats given propofol [130]. We recently showed in rats that general propofol anesthesia independent of the time-of-day of its administration (injections at ZT6. thereby we still do not know if the anesthesic effects on circadian rhythms are dependent of the treatmenttime because there is no data on anesthesia performed during the night in humans. 4. it has been shown. As shown above. it has first been shown that the levels of plasma cortisol. These data suggest that general anesthesia may act as an external factor that could disturb the circadian time structure. in their real-life conditions.2. Whether such effects are also present with other anesthetics is unknown though a recent study on sevoflurane (administered during the rest period) showed a decrease in the expression of the clock gene per2 which is involved in the regulation of the clock in rodents [135]. we examined very recently in our laboratory general propofol anesthesia effects on melatonin secretion in vivo on the circadian profile of plasma melatonin [134]. 11). cardiac surgery. without any surgery [132]. Evidently. Since interactions between melatonin and the rest–activity cycle are well known [145]. its effects on the biological system is of particular relevance and it is of interest to note that a link between post-operative high levels of plasma cortisol and post-operative cognitive dysfunction has been suggested [144]. Anesthetic effects on hormonal secretions 4. 4.4.e. both of which did not affect corticosterone secretion in rabbits during anesthesia but in contrast increased hormone secretion during the first 60–120 min recovery period [142].m.1. a decrease in the strength of coupling of the rhythm to supposedly stable environmental factors and increased fragmentation of the rhythm after anesthesia. The rest–activity rhythm was less strongly coupled to Zeitgebers in the days following anesthesia with a decrease in interdaily stability parameters (the strength of coupling the rhythm to supposed stable environmental Zeitgebers) and increased interdaily variability (the extent and transition between rest and activity) during the 72 h following general anesthesia [132] (Fig.

Clock. Firstly.940 Y. concerning inhalation anesthetics. Indeed. Clock and BMAL1.05) to mean values between propofol and Intralipids treatment. SCN) is regulated at the gene level. Per3. / Advanced Drug Delivery Reviews 62 (2010) 928–945 Fig. it was shown that sevoflurane impacts the expression of clock gene Per 2 by decreasing its expression level in the whole brain when rats are anesthetized during light period (6-h anesthesia). it appears that general anesthesia induces a desynchronization of the circadian time structure during the post-anesthesia period. The alternative mechanism might be a direct effect on clock genes expression within the SCN. The importance of the desynchronization is dependent on the time of administration of the general anesthetic. The effects of GABA infusion are dependent upon the circadian stage [147]. . even if it has no impact on the other clock genes studied (Per1. For (A) and (B). 24 h propofol anesthesia effects on corticosterone and ACTH secretions. some studies show that general anesthetics (inhaled gases as well as intravenous) impact the expression of several clock genes in rat brains during rest period [150–152]. To date. This result has been obtained only at one circadian time of GABAergic agonist administration. values are mean ± SEM. One hypothesis is that propofol. these are generated by an auto-feedback loop system in which the transcription of clock genes is suppressed by clock gene products that play a central role in oscillation [150]. (B) 24 h post propofol anesthesia or intralipids effects on ACTH concentrations at one injection point (ZT16). the desynchronization of the circadian rhythms is bigger when the anesthesia is performed during the rest period than during the activity period. Anesthetics effects on clock genes The circadian clock (suprachiasmatic nucleus. has an inhibitory effect on the outputs from SCN to the paraventricular nucleus. From Dispersyn et al. 4.149]. Bmal1. 11. Cosinor analysis (a procedure for the analysis of biological rhythms based on the fitting of a cosine wave to the raw data) suggested that propofol anesthesia induces a phase advance of the circadian secretion of melatonin. the precise cellular mechanisms involved in circadian clock desynchronization induced by general anesthesia remain unknown. from the pineal gland. Touitou et al. The main clock genes identified at this time are Period (Per). Asterisks denote significant differences (p b 0. [133]. The transcription of clock genes generates oscillations. Recent data showed that GABAergic agonists administered during the mid-subjective day induce a phase advance of circadian rhythm and modify the expression of clock genes per1 and per2 within the SCN [148. so we do not know if this result can be obtained at other circadian times.5. However. In conclusion of all the animals and humans studies. inducing a phase advance of the circadian rhythms. a GABA agonist. However. few data on the effects of general anesthesia on clock genes as well in human than in animal model are available. (A) 24 h prolonged effects of a single propofol or control injection on rats (n = 72) corticosterone concentrations at one injection time (ZT16). Our results demonstrate that melatonin secretion is disrupted during the 24 h following propofol anesthesia. Cryptochrome(Cry).

genuine mirrors of an adaptation feature to constantly changing surroundings. The effects of anesthetics associated with opioids remain unknown. Secondly. inhaled as well as intravenous general anesthetics act on the main clock genes like Period gene even if studies are rare and performed on the whole brain of rats. the authors acknowledge that the data obtained can result from the summation of both suppression and activation in different neurons and do not reflect the expression of these genes in SCN [150]. Cortisol and melatonin are also among the main biological marker rhythms. which drives the basal hypothalamopituitary-adrenal (HPA) rhythmicity. Motor activity. is the SCN that is responsible of many aspects of circadian rhythmicity [1–3]. The persistence of a circadian rhythmicity in an environment without any known external time cues suggests that there is an internal time-keeping system called the biological clock which. plasma cortisol and melatonin patterns are important marker rhythms. These data were collected in rats still anesthetized under 6-hour administration of sevoflurane. the sleep–wake cycle. Entrainment of the cortisol rhythm by the light–dark cycle is mediated by the eyes and transmitted to the SCN. Unfortunately this study provides no data on the long-lasting effect of sevoflurane on Per2 expression level after awakening from anesthesia. Finally. In conclusion.Y. Indeed. we need the use of circadian markers allowing the circadian time structure of this organism to be determined. 12. The issue with these two studies is that the results are obtained on whole brain and do not allow the localization of gene expression. the L/D cycle is transposed in biological representations. 5. Rev-erb-alpha) [152]. The issue in this study is the same as that in the two previous ones. Indeed. mostly consequences of the earth's revolution around its axis (light–dark cycle). From Dispersyn et al. meal schedules. Biological rhythms are characterized by their ability to be entrained by external environmental cues. To ascertain whether an organism is synchronized (or desynchronized). in mammals. [134]. Values are given as mean □ SD. and appear to modify the photic responsiveness of the circadian pacemaker as assessed by clock genes. the administration of the opioid fentanyl decreased light-induced Per1 gene expression during night in Syrian hamsters in the SCN [153]. opioids are often used in combination with anesthetics. The circadian rhythm of cortisol is driven by the endogenous oscillator situated in the hypothalamic suprachiasmatic nuclei (SCN) [159]. another study showed that the Per2 gene expression level was decreased 24 h after anesthesia with sevoflurane during the rest period in rat whole brain [151] and thus demonstrated a long-lasting effect of anesthesia at the molecular level. Locomotor activity and core body temperature are often used in experimental protocols [154–156].05) to mean values between propofol and control. concerning intravenous anesthetics. For living organisms. the circadian rhythms. Touitou et al. Many biological functions show circadian rhythms. and not yet on the SCN. as data were obtained on the whole brain. . body temperature. and seasonal factors related to modifications in photoperiod and outside temperature. / Advanced Drug Delivery Reviews 62 (2010) 928–945 941 Fig. with rhythmicity a fundamental property of living matter. Thus the differences in gene expression do not reflect the expression levels of these genes in the suprachiasmatic nucleus (SCN). that is their temporal variation may be considered as a cyclic function with a periodicity ranging between 20 and 28-h. Conclusions and perspectives Most living beings change their behavior on a daily basis (24-h). * Significant differences (P b 0. Our organism is synchronized when it works in harmony (in synchrony) with environmental factors called synchronizers which include the light–dark cycle. This raises a question about the relation between the rhythms of melatonin and cortisol. We found in healthy subjects that those subjects with a slightly variable melatonin circadian rhythm . Dbp and tef (composites of the core oscillating loops in the SCN) brain expression levels were equally decreased by propofol anesthesia. This relation has been studied in blind subjects and seems to be highly correlated [160]. The circadian rhythm of body temperature is generated by an endogenous component but is also dependent on motor activity [157. However. which is the primary circadian pacemaker in mammals. Effects of propofol anesthesia or control treatment on melatonin secretion at one Zeitgeber time of injection (ZT16) on peripheral melatonin secretion. a similar experimental approach showed that a 6-hour administration of propofol during the rest period decreased Per2 gene expression levels in rat whole brain [150]. The daily rhythmicity is thus the result of the combined action of the endogenous biological clock(s) and environmental time cues. The circadian rhythm of melatonin is also generated by the SCN [159] and entrained by the light–dark cycle via the retino-hypothalamic tract. to set a “balanced” anesthesia.158].

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