Biomedical subjects

Y Touitou

Publications and source records attributed to Y Touitou.

At least 19 recordsLinked to original sources

PubMed2003

Effect of age and photoperiodic conditions on metabolism and oxidative stress related markers at different circadian stages in rat liver and kidney.

It has been shown that some cytochrome P450-dependent enzyme activities could present daily fluctuations, particularly CYP3A isoenzymes which are enhanced during the dark period. The aim of this study was to investigate whether age and photoperiodic conditions at different circadian stages could influence these fluctuations. Young mature (10 weeks) and old (22 months) Wistar rats were initially exposed to light-dark cycles 12:12 during 4 weeks, and secondly 18:6 for either one week or six weeks. Erythromycin N-demethylase (CYP3A-dependent), 7-ethoxycoumarin O-deethylase (CYP1A-dependent) and aniline 4-hydroxylase (CYP2E-dependent) activities were determined in liver and kidney microsomes at different hours after darkness onset (HADO). In addition, liver and kidney GSH, GSHPx, ATP, TBARS were determined. During the LD 12:12 cycle, while no significant modification was observed in CYP1A- and 2E-dependent enzyme activities as functions of HADO, erythromycin N-demethylase activity (CYP3A-dependent) showed a significant increase during the second third of the dark period in both young and old rats. After switching to a LD 18:6 cycle, this variation was still observed during second third of the dark period, to a lesser but still significant degree, with no difference between one week and six weeks exposure to the new photoperiod. It can be noted that the old rats showed a significantly lower level of erythromycin N-demethylase activity than the young rats, in parallel to a decrease in GSH, GSHPx and ATP, and an increase in TBARS. These results confirm the lower resistance of old animals to oxidative stress. The observed variations in metabolism parameters underline the need for study designs in pharmaco-toxicology taking into account the possible risks induced by circadian changes, especially in aged subjects.

Aging↗

PubMed2003

Effect of a synthetic pineal tetrapeptide (Ala-Glu-Asp-GLy) on melatonin secretion by the pineal gland of young and old rats.

The pineal gland contains many peptides known to be implicated in melatonin production. We examined the effects of a synthetic pineal tetrapeptide Ala-Glu-Asp-Gly on melatonin secretion by the pineal gland. The tetrapeptide effects on pineal gland melatonin secretion were studied in young (9 weeks) and old (27 months) male Wistar rats using a perifusion device. Pineal tetrapeptide at the concentrations used (10(-4) to 10(-6) M) had no significant effect upon melatonin secretion whatever the age of the animals, young or old. We also looked at the effect of the tetrapeptide on pineal melatonin stimulated by a beta-adrenergic agonist, isoproterenol. We found that isoproterenol-induced melatonin increase was not modified by the tetrapeptide. Our results suggest that the pineal tetrapeptide Ala-Glu-Asp-Gly, does not seem to play a role, at least in vitro, in the control of melatonin secretion by the rat pineal gland.

Adrenergic beta-Agonists↗

PubMed2003

Magnetic field (50 Hz) increases N-acetyltransferase, hydroxy-indole-O-methyltransferase activity and melatonin release through an indirect pathway.

PURPOSE: To examine whether magnetic fields (MF) affect N-acetyltransferase (NAT) and hydroxy-indole-O-methyltransferase (HIOMT) activity directly or exert their effect through a cellular pathway that indirectly regulates the activity of these enzymes and melatonin release. MATERIALS AND METHODS: The pineal glands from Wistar rats were isolated at 10:00 h and exposed to MF (50 Hz, 1 mT) for 4 h in vitro, with or without 1 micro M norepinephrine. An additional group of pineals was exposed to MF 30 min before norepinephrine addition. The direct effect of MF on the activity of the enzymes was studied in sonicated glands exposed to MF. NAT activity, HIOMT activity and melatonin release were determined. RESULTS: In pineal glands isolated in the morning, 4-h in vitro exposure did not affect the basal release of melatonin from the pineal gland as well as the basal NAT and HIOMT activities. Pineal gland exposure to MF 30 min before norepinephrine addition significantly (p<0.05) increased NAT activity, HIOMT activity and melatonin release (p<0.05). These effects were not observed in pineals co-treated with MF and norepinephrine or in sonicated glands exposed to MF. CONCLUSIONS: The results suggest that in pineals isolated in the morning, 4-h MF exposure changes melatonin release by affecting the signal transduction pathway leading from the norepinephrine receptor to NAT and HIOMT and not via a direct effect at the enzyme levels.

Acetylserotonin O-Methyltransferase↗

PubMed2002

Effect of a short photoperiod on circadian rhythms of body temperature and motor activity in old rats.

Circadian rhythms of body temperature and motor activity were documented in young and old rats (four 8-week-old and five 22-month-old male Wistars, implanted with telemetric probes and housed in a chronobiological facility) under two different photoperiod conditions. The animals were maintained in a light:dark (LD) cycle of 12 h each (LD 12:12) for 4 weeks and then exposed to a LD 6:18 cycle for 7 weeks to assess the effect of age on the desynchronization of the temporal structure of the rhythms. In old rats under LD 12:12, the power of the 24-h component and the circadian amplitude of body temperature and motor activity were markedly lower than in the young and both rhythms were phase-advanced. After the shift to LD 6:18, the circadian rhythmicity was maintained for both variables and the same phase delay (+5+/-1 h) was observed in both age groups, as was a gradual expansion of the patterns of both functions with the longer night. The photoperiod reduction (6 weeks under LD 6:18) did not modify the power of the 24-h component of body temperature and motor activity in old rats. In young rats, however, the power and amplitude of the 24-h component of motor activity rhythm fell to the levels of those in old rats, while the power of the 24-h component of body temperature rhythm and the amplitude did not change. Our data show that the circadian rhythm of motor activity, but not of body temperature, responds age dependently to a photoperiod reduction.

Aging↗

PubMed2001

Effects of electric and magnetic fields from high-power lines on female urinary excretion of 6-sulfatoxymelatonin.

In 1998, the authors studied the effect of residential exposure to electric and magnetic fields from high-power lines on female urinary excretion of 6-sulfatoxymelatonin (6-OHMS) in the Quebec city, Canada, metropolitan area. A sample of 221 women living near a 735-kV line was compared with 195 women the same age living away from any power lines. Participants provided morning urine samples on 2 consecutive days and wore a magnetic dosimeter for 36 consecutive hours to measure personal magnetic exposure. The indoor electric field was assessed by spot measurements. After adjustment for other factors associated with low melatonin secretion, such as medication use or light exposure, nighttime concentration of 6-OHMS was similar in the two groups. When either 24-hour or sleep-time exposure to magnetic field or electric field measurements was used, no exposure-effect relation was evident. However, the trend of decreasing 6-OHMS concentration with age was more pronounced for women living near the lines, as was a lower 6-OHMS concentration in women with high body mass index. Chronic residential exposure to magnetic fields from high-power lines may accentuate the decrease in melatonin secretion observed in some vulnerable subgroups of the population.

Adult↗

PubMed2001

Circadian rhythms of body temperature and motor activity in rodents their relationships with the light-dark cycle.

In rodents, the alternation of light and dark is the main synchronizer of circadian rhythms. The entrainment abilities of the LD cycle could be estimated by experimental modifications of the photoperiod and by following the subsequent temporal distribution of a circadian rhythm. The rate of reentrainment of a rhythm is determined by the nature of the studied variable, by the direction (advance or delay) and the magnitude (or value) of the phase shift. In rodents, core body temperature and motor activity are known to be well synchronized with each other under L:D 12:12 and under constant conditions (LL or DD). There are clear evidences that the circadian pattern of motor activity is generated by two oscillators, one from dusk signal and the other from dawn signal. Whether the circadian rhythms of body temperature and motor activity are generated by a common circadian mechanism or controlled by separate ones still remains unknown. The purpose of this review is to summarize the results obtained on the circadian rhythms of body temperature and motor activity throughout the daily cycle in order to clarify the relationships between these two functions.

Animals↗

PubMed2001

Ramadan fasting alters endocrine and neuroendocrine circadian patterns. Meal-time as a synchronizer in humans?

Muslims must refrain from eating, drinking, smoking, and sexual relations from sunrise to sunset during the month of Ramadan. Serum concentrations of melatonin, steroid hormones (cortisol, testosterone), pituitary hormones (prolactin, LH, FSH, GH, TSH) and thyroid hormones (free thyroxin and free triiodothyronine) were documented around the clock at six 4-hourly intervals before Ramadan began and on the twenty-third day of Ramadan (daytime fasting). Time series were analysed with repeated measures ANOVA. Statistically significant differences were found in some variables: the nocturnal peak of melatonin was diminished and may have been delayed; there was a shift in the onset of cortisol and testosterone secretion; the evening peak of prolactin was enhanced, FSH and GH rhythmic patterns were affected little or not at all by Ramadan fasting and only the serum TSH rhythm was blunted over the test time span. These data show that daytime fasting, modifications in sleep schedule and psychological and social habits during Ramadan induce changes in the rhythmic pattern of a number of hormonal variables.

Adult↗

PubMed2001

Enhanced cortical extracellular levels of cholecystokinin-like material in a model of anticipation of social defeat in the rat.

The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats.

Aggression↗

PubMed2001

Melatonin synthesis in the rat harderian gland: age- and time-related effects.

The Harderian gland is considered as an extrapineal source of melatonin. In the pineal gland, melatonin is known to present a circadian rhythm with high concentration during nighttime in all species studied. We determined in Wistar male rats the effects of age and time of day on melatonin synthesis in the Harderian gland. We compared Harderian gland melatonin content and the hormone synthesizing enzymes, serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase, in young (4 months) and old (22 months) animals at six circadian stages and found that melatonin synthesis in the Harderian gland was unaffected by age. We also studied the Wistar rat Harderian gland at ten different circadian stages and found that the Harderian gland did not exhibit a daily rhythm in its melatonin content. This study shows that, by contrast to the pineal gland, melatonin in Wistar rat Harderian gland does not exhibit daily variations and that aging does not affect the melatonin content of the gland.

Acetylserotonin O-Methyltransferase↗

PubMed2001

Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands.

RATIONALE: Pineal and Harderian gland melatonin production as well as plasma melatonin levels were investigated in male Wistar rats (12 weeks old) after administration of diazepam, a benzodiazepine widely used as anxiolytic. OBJECTIVE: The present study investigates the effects of a chronic administration of diazepam on pineal and Harderian gland melatonin contents. METHODS: Diazepam was administered subcutaneously, for 21 days, at a dosage of 3 mg/kg body weight per day, 1 h before the onset of darkness. RESULTS: Diazepam clearly affected pineal melatonin biosynthesis and plasma melatonin levels. Diazepam reduced the pineal melatonin content (by a factor of 2) and the activity of N-acetyltransferase (NAT) (by a factor of 3.5), as well as plasma melatonin levels (by a factor of 1.5), but had no effects on pineal hydroxyindole-O-methyltransferase activity. By contrast to the pineal gland, diazepam failed to affect the Harderian gland melatonin content. CONCLUSIONS: Our results suggest that the inhibition of melatonin production induced by diazepam in vivo may be due to a direct action of this benzodiazepine on the pineal gland, through its action on NAT, the key enzyme of melatonin synthesis, and that the control of melatonin production in the Harderian glands may be different from that observed in the pineal gland.

Acetylserotonin O-Methyltransferase↗

PubMed2001

[Alcohol, chronobiology and sleep].

Chronobiology is the scientific discipline of biologic rhythm study. Applications of the emerging concepts of chronobiology are now use in several fields of clinical medicine. Alcohol related disorders seems to be clarified with the main concepts of chronobiology. Thus chronopharmacology (specially chronokinetics and time-related differences in drug effects) clears up variations of blood alcohol levels and toxicity of ethanol during the 24 h, chronesthesy explains the action of ethanol on biological rhythms of hormone secretions and sleep, and the concept of chronopathology seems to be apply to alcohol dependence. We review in this article some applications in alcohol related disorders of the main concepts of chronobiology.

Alcoholism↗

PubMed2001

Human aging and melatonin. Clinical relevance.

Melatonin is a hormone produced mainly by the pineal gland and secreted primarily at night, when it reaches levels 10 times higher than those present in the daytime. The highest melatonin levels are found in children younger than 4 yr; thereafter melatonin levels begin to decline with age. As a chronobiotic, melatonin acts on sleep by phase-advancing or delaying the sleep--wake cycle so that sleep onset occurs earlier or later than usual. Beneficial effects of melatonin have been observed in delayed and advanced sleep phase syndromes. These effects depend on the time that the hormone is administered. Melatonin is also used for jet lag and has been tried in shift workers and night workers to re-entrain their desynchronized rhythms. Melatonin also has free radical-scavenging properties that have primarily been observed in vitro at pharmacological concentrations.

Aging↗

PubMed2001

Is melatonin circadian rhythm a physiological feature associated with healthy longevity? A study of long-living subjects and their progeny.

The study investigates the circadian rhythm (CR) of urinary 6-sulphatoxy-melatonin (aMT6s) in long-living (longevous) subjects and their progeny. The aim is to detect whether or not the melatonin CR is a physiological feature associated with healthy longevity. The aMT6s CR was investigated in 10 longevous subjects, 8 of their children and 9 of their grandchildren, all in good health. Control data were obtained respectively from 13 adult subjects and 9 young subjects, in good health, but characterized by a negative family history for longevity. All the subjects were born and living in the same city. The study was performed in the summer of 1996. The aMT6s CR was found to persist in longevous subjects, being characterized by a lower mesor and amplitude. The aMT6s CR was found not to show properties consistently different in children and grandchildren as compared respectively to their adult and young controls. Because of its preservation in longevous subjects, it can be argued that the melatonin CR is a physiological feature associated with healthy longevity. Because of the comparability of aMT6s CR in children and grandchildren, with respect to their controls without a positive family history of longevity, it can be argued that the melatonin CR is not a marker that can be used for an earlier identification of the candidates for longevity.

Adult↗

PubMed2001

Role of school schedule, age, and parental socioeconomic status on sleep duration and sleepiness of Parisian children.

The aim of the study was to assess the duration and quality of sleep of prepubertal (Tanner Scale level 1) physically and mentally healthy children as a function of school schedule (4 versus 4.5 days per week), age and grade (median age of 9.5 years for 4th grade versus median age of 10.5 years for 5th grade), school district (wealthy versus nonwealthy) in Paris, France, and parental socioeconomic status (high, medium, or low). We studied 51 girl and 44 boy volunteer pupils with written parental consent. The study lasted 2 weeks during the month of March. During the first study week, the children attended school 4.5 days, and during the second week, they attended school only 4 days without difference in the length of the school day. A sleep log was used to ascertain time of lights off for sleep and lights on at awakening, nighttime sleep duration, and self-rated sleep quality. A visual analog scale (VAS) was also used by pupils to self-rate the level of perceived sleepiness at four specific times of the school day. Conventional statistical methods (e.g., t and chi2 tests) were used to examine differences in mean values. Sleep duration, self-rated sleepiness, and subjective sleep quality were comparable (P > .05) by gender, school schedule, school district, and parental socioeconomic status. Overall, the sleep of this sample of Parisian children around 10 years of age was rather stable in its duration and timing, suggesting flexibility to adjust to the different school schedules.

Age Factors↗

PubMed2001

The effect of alcohol consumption on the circadian control of human core body temperature is time dependent.

The few controlled studies dealing with the action of alcohol on core body temperature in humans have focused on the effect of a single dose of ethanol and reported that it has a hypothermic effect. No studies report the effects of repeated ethanol intake over a 24-h period, a pattern of consumption much closer to the clinical condition of chronic alcoholism. We therefore designed a trial in which alcohol was repeatedly and regularly administered, with a total dose of 256 g. Nine healthy male volunteers (mean age 23.3 +/- 2.9 yr; range 21-30) each served as his own control. The circadian temperature rhythm was studied by a single-blind, randomized, crossover study that compared a 26-h alcohol session to a 26-h placebo session. The trial controlled for so-called masking effects known to affect temperature. The volunteers were in bed; the ambient temperature was maintained between 20 and 22 degrees C. Meals were standardized. And light was controlled during the night. All sessions took place between November and April. The two sessions were separated by 2 to 5 wk. Rectal temperature was monitored every 20 min throughout the trial. We found the standard hypothermic effect of alcohol in the early hours of the trial, during the daytime, but our principal result is that alcohol consumption induced a very significant hyperthermic effect (+0.36 degrees C) during the night and thereby reduced the circadian amplitude of core body temperature by 43%. The dramatic decrease of the amplitude of circadian temperature rhythm that we observed may explain, at least in part, some clinical signs observed in alcoholic patients, including sleep and mood disorders. We suggest that jet lag, shift work, and aging, which are known to alter body temperature, are aggravated by alcohol consumption.

Adult↗

PubMed2000

Evidence of prooxidant and antioxidant action of melatonin on human liver cell line HepG2.

The aim of this study was to evaluate melatonin cytotoxicity by measuring its effects on various cellular targets. Cell viability, intracellular reduced glutathione (GSH) level, and reactive oxygen species (ROS) production were assessed in the human liver cell line (HepG2), after incubation with increasing melatonin concentrations (0.1-10,000 microM). The incubation times tested were 24, 72, and 96 h for cell viability and intracellular GSH level, and 15 and 45 minutes for ROS production. Cellular target evaluations were possible in living cells by means of a new microplate cytofluorimeter. This technology was suitable for the assessment of cell viability, GSH level, and ROS overproduction with, respectively, neutral red, monochlorobimane (mBCl), and 2',7'-dichlorofluorescin diacetate (DCFH-DA) fluorescent probes. At the lowest melatonin concentrations (0.1-10 microM) and for a relatively short incubation time (24 h), the antioxidant effect of melatonin was revealed by an increased intracellular GSH level, associated to cell viability improvement. In contrast, after longer incubation (96 h), cell viability significantly decreased with these lowest melatonin concentrations (0.1-10 microM). Moreover, high melatonin concentrations (1,000-10,000 microM) induced GSH depletion. This oxidative stress is associated with ROS overproduction from 10 microM after only 15 minutes of incubation. This dual effect is strong evidence that, in vitro, melatonin can be both antioxidant and prooxidant on the human liver cell line, depending on the concentration and incubation time.

Antioxidants↗

PubMed2000

DHEA-sulfate causes a phase-dependent increase in melatonin secretion: a study of perifused rat pineal glands.

Steroid hormones affect various metabolic activities, including melatonin synthesis, in mammals and nonmammals. We report here the effects of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), two steroids with weak androgen potency, on the levels of isoproterenol-stimulated melatonin released by perifused rat pineal glands removed in the middle of the light and dark spans [7 and 19 Hours After Light Onset (HALO), respectively] in a L/D 12:12 regimen. DHEA-S but not DHEA was found to have a direct action on beta-adrenergic-stimulated melatonin release. DHEA-S increased melatonin secretion (by 50-80%) dose-dependently in pineals obtained during the light span. This effect depended on the circadian stage, because at night (19 HALO), only the highest concentration (10(-3) M) of DHEA-S increased melatonin secretion (by 25%). In contrast, DHEA had no effect on melatonin release in pineals obtained during the light span. This work shows that DHEA-S but not DHEA was able to stimulate melatonin secretion by adrenergic-stimulated pineals removed during the light phase. It also suggests that the effects observed, or their intensity, or both depend on the circadian stage.

Adrenergic beta-Agonists↗

PubMed2000

Progesterone inhibits, on a circadian basis, the release of melatonin by rat pineal perifusion.

The effects of 10(-6) and 10(-9) M of progesterone were documented on isoproterenol-stimulated melatonin release by perifused pineal glands removed from female rats in diestrous at two different times of a 12 : 12 h light/dark cycle, 7 and 19 h after light onset (which corresponds to daytime and nighttime, respectively), to look for the existence of a circadian stage-dependence of the hormone effects. Three weeks before the experiment, the rats were synchronized with a 12 : 12 lighting regimen. Progesterone decreased by approximately 50% the release of melatonin during the light span, but not during the dark span. These results show the direct effects of this ovarian hormone on pineal melatonin release and strongly suggest a time-related effect of progesterone on pineal function.

Animals↗