Biomedical subjects

Daniel P Cardinali

Publications and source records attributed to Daniel P Cardinali.

At least 55 records · Page 3Linked to original sources

PubMed2003

Melatonin increases oestradiol-induced bone formation in ovariectomized rats.

To assess the effect of melatonin on bone metabolism in ovariectomized rats, receiving oestradiol therapy or not, melatonin was administered in the drinking water (25 microg/mL water) and oestradiol (10 microg/kg body weight) or vehicle was given subcutaneously 5 days/week for up to 60 days after surgery. Urinary deoxypyridinoline (a marker of bone resorption) and circulating levels of bone alkaline phosphatase activity (a marker of bone formation), as well as serum calcium and phosphorus levels, were measured every 15 days. Bone area (BA), bone mineral content (BMC), bone mineral density (BMD) and total body fat (expressed as 100 g body weight) were measured by dual-energy X-ray absorptiometry at the end of the experiment. Body weight and total body fat were augmented after ovariectomy, and decreased after melatonin or oestradiol treatment. The effect of melatonin on body weight was seen in sham-operated rats only. Ovariectomy augmented, and melatonin or oestradiol lowered, urinary deoxypyridinoline excretion. This effect of melatonin and oestradiol was seen mainly in ovariectomized rats. The efficacy of oestradiol to counteract ovariectomy-induced bone resorption was increased by melatonin. Melatonin or oestradiol lowered serum bone alkaline phosphatase activity. Melatonin inhibition was seen mainly on the increase of bone alkaline phosphatase activity that followed ovariectomy. Serum phosphorus levels decreased after melatonin administration and were augmented after oestradiol injection; overall, melatonin impaired the increase of serum phosphorus caused by oestradiol. Ovariectomy decreased, and oestradiol increased, serum calcium levels while melatonin augmented serum calcium in sham-operated rats only. On day 60 after surgery, BMD and content decreased after ovariectomy and were increased after oestradiol injection. Melatonin augmented BA of spine and BMC of whole of the skeleton and tibia. The highest values observed were those of rats treated concurrently with oestradiol and melatonin. The present results indicate that: (i) melatonin treatment restrained bone remodelling after ovariectomy; (ii) the effect of melatonin required adequate concentrations of oestradiol; (iii) melatonin augmented oestradiol effects on bone in ovariectomized rats; (iv) a counter-regulation by melatonin of the increase in body fat caused by ovariectomy was uncovered. The melatonin doses employed were pharmacological in terms of circulating melatonin levels but not necessarily for some other fluids or tissues.

Animals↗

PubMed2003

Melatonin effects on bone: experimental facts and clinical perspectives.

Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post-menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin-bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose-dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c-peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone-protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.

Aged↗

PubMed2003

Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure.

OBJECTIVE: To assess urinary 6-sulfatoxymelatonin excretion in patients admitted to the hospital because of congestive heart failure (CHF). METHODS: Urinary 6-sulfatoxymelatonin was measured by a specific radioimmunoassay in 33 hospitalized patients with CHF and in 146 healthy ambulatory volunteers. Individuals with hepatic or renal failure were excluded from the sample. Data were analyzed by the Mann-Whitney test and regression analysis. RESULTS: 6-Sulfatoxymelatonin levels were significantly lower in CHF patients than controls (median 2.6 vs 6.02 microg, p < 0.0001). This decrease was observed regardless of beta-adrenergic blocker or benzodiazepine medication. A significant decrease in 6-sulfatoxymelatonin excretion occurred with age. There were no significant differences in urinary 6-sulfatoxymelatonin levels between chronic and acute CHF patients. CONCLUSIONS: The results suggest that circulating melatonin levels are low in patients with CHF. Such a decrease may precede aggravation of heart failure.

Adrenergic beta-Antagonists↗

PubMed2003

Effect of unilateral superior cervical ganglionectomy on mandibular bone in rats.

OBJECTIVE: To assess the effect of local sympathectomy on mandibular bone during tooth eruption in rats. METHODS: The effect of a unilateral superior cervical ganglionectomy (Gx) on morphometry of ipsi- and contralateral mandible and volumetric bone density (as assessed by peripheral computed tomography) was examined 30 days after surgery. RESULTS: Only a few mandibular morphometric parameters decreased significantly after denervation in rats subjected to a unilateral Gx and a contralateral sham-operation. Mandibular volumetric bone density decreased significantly after sympathetic denervation. In a second experiment, carried out under conditions of unilateral unimpeded eruption of incisors performed ipsilaterally or contralaterally to a unilateral Gx, a significant interaction "denervation x type of eruption" was found for most morphometric parameters. Further analysis indicated higher morphometric indexes in denervated mandibles than in the innervated ones under impeded incisor eruption conditions, and lower morphometric indexes in denervated mandibles than in the innervated ones under unimpeded incisor eruption conditions. Unimpeded eruption augmented total volumetric bone density providing the innervation was intact and caused opposite effects on cortical volumetric bone density in the presence of innervation (increase) or absence of innervation (decrease). Trabecular volumetric bone density decreased significantly after sympathetic denervation. CONCLUSION: The results support a role of the sympathetic nervous system in the regulation of bone remodeling.

Animals↗

PubMed2003

In vitro effect of melatonin on oxygen consumption in liver mitochondria of rats.

OBJECTIVE: To examine the in vitro effect of melatonin on rat mitochondrial liver respiration. METHODS: Oxygen consumption by liver mitochondria was measured polarographically in the presence of one of the following Krebs' cycle substrates: Lsuccinate, DL-3- beta-hydroxybutyrate or L-malate. Respiratory velocities at rest (state 4) and during rapid respiration in the presence of substrate and adenosine diphosphate (state 3) were measured in the presence of 10 (-9)-10(-3) M concentrations of melatonin. RESULTS: In vitro melatonin (10(-7)-10(-3) M) reduced state 3 mitochondrial respiration. Basal, state 4 respiration was not affected by melatonin. Consequently, control respiratory index (i.e., the ratio of state 3 to state 4 respiration) was inhibited by melatonin with a threshold at 10(-7) M concentration. CONCLUSION: The ability of melatonin to curtail acutely the stimulation of oxygen consumption in liver mitochondria may protect the mitochondria from excessive oxidative damage.

3-Hydroxybutyric Acid↗

PubMed2002

Effect of melatonin on changes in locomotor activity rhythm of Syrian hamsters injected with beta amyloid peptide 25-35 in the suprachiasmatic nuclei.

1. Alzheimer's disease is associated with circadian rhythm disturbances, probably because of beta amyloid-induced neuronal damage of hypothalamic suprachiasmatic nuclei (SCN). 2. Since there is no published study on the circadian consequences of injecting beta amyloid peptide in experimental animals, one objective of the present study was to examine circadian locomotor activity in Syrian hamsters injected with beta amyloid peptide 25-35 into both SCN. 3. Because one of the proposed therapies for circadian alterations in dementia is the administration of melatonin, a chronobiotic agent with antioxidant properties, the preventive effect of melatonin on the circadian changes produced by beta amyloid microinjection into SCN was also assessed. 4. Wheel running activity was recorded by using the Dataquest III system in male golden hamsters kept under 14:10 light-dark photoperiods. Animals received microinjections of beta amyloid peptide 25-35 (100 microM solution, 1 microL) or saline in each SCN. Only those animals with neuronal lesions larger than 10% of SCN after beta amyloid injection were considered for further analysis. 5. To assess the effect of melatonin on beta-amyloid peptide activity, melatonin was given in the drinking water (25 microg/mL) starting 15 days in advance to the microinjection of beta amyloid peptide into SCN. 6. Beta amyloid-treated hamsters exhibited a significant phase advance of onset of running activity of about 22 min as compared to saline-injected animals. They also showed a significantly greater variability in onset time of wheel running activity, mainly evident from 6 to 15 days of treatment. 7. Melatonin administration in the drinking water prevented the phase advance of onset time and the increased variability of onset time brought about by beta amyloid peptide. 8. The results support the existence of a neuroprotective effect of melatonin on beta amyloid-induced circadian changes in hamsters.

Alzheimer Disease↗

PubMed2002

Vascular reactivity in diabetic rats: effect of melatonin.

The aim of the present study was to evaluate the in vitro contractile response of rat aorta in mild and severe type I diabetes and the effect of melatonin on it. Aortic rings were obtained from male Wistar rats injected with streptozotocin 8-12 wks earlier. Rats were divided into three groups: non-diabetic rats (NDR), mildly diabetic rats (MDR) and severely diabetic rats (SDR). Dose-response curves for acetylcholine-induced, endothelium-related relaxation of aortic rings (after previous exposure to phenylephrine) and for serotonin-induced vasoconstriction were conducted in the presence or absence of 10-5 mol/L melatonin. This protocol was repeated with rings preincubated in a high glucose solution (44 mmol/L). The contractile response to phenylephrine decreased in SDR, an effect counteracted by preincubation with high glucose. Melatonin decreased phenylephrine-induced vasoconstriction in MDR and counteracted the effect of high glucose in SDR. Acetylcholine-evoked relaxation decreased significantly after exposure to a high glucose in SDR, this effect being counteracted by melatonin. Serotonin-induced vasoconstriction decreased in SDR and augmented in MDR, but only after exposure to high glucose. Melatonin reduced the maximal tension of aortic contraction after serotonin in MDR, both under basal conditions and after preincubation in a high glucose solution. The results support the existence of differences in vasomotor responses as a function of the diabetes state and of an improvement of contractile performance in diabetic rats after exposure to melatonin at a pharmacological concentration (in terms of circulating melatonin levels but not necessarily for some other fluids or tissues).

Acetylcholine↗

PubMed2002

A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes.

Rapid transmeridian translocation through multiple time zones has a negative impact on athletic performance. The aim of the present study was to test the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization of a group of elite sports competitors and their coaches to a westerly transmeridian flight comprising of 12 time-zones. Twenty-two male subjects were included in the study. They were professional soccer players and their coaches who travelled to Tokyo to play the final game of the Intercontinental Coup. The day prior to departure, urine was collected from each subject from 18:00 to 06:00 hrs to measure the melatonin metabolite 6-sulphatoxymelatonin. Participants were asked to complete sleep log diaries from day 0 (preflight) to the day before returning to Buenos Aires (day 8). All subjects received 3 mg of melatonin p.o. daily at expected bedtime at Tokyo immediately after leaving Buenos Aires. Upon arrival at Tokyo the subjects performed a daily physical exercise routine outdoors at two restricted times of the day (from 08:00 to 11:00 hrs in the morning and from 13:00 to 16:00 hrs in the afternoon). Exposure to sunlight or physical exercise at other times of the day was avoided. Except for the number of awakenings (which increased on days 1 and 3) and sleep latency (which decreased on days 2, 6 and 8), there was an absence of significant changes in subjective sleep parameters as compared with preflight assessment. Sleep quality and morning alertness at Tokyo correlated significantly with preflight 6-sulphatoxymelatonin excretion. Mean resynchronization rate of sleep-wake cycle to the 12 hr-time shift was 2.13 +/- 0.88 days, significantly different from the minimal resynchronization rate of 6 days expected after a 12-time-zones flight. The results indicate that the combination of melatonin treatment, an appropriate environmental light schedule and timely applied physical exercise can be useful to help elite athletes to overcome the consequences of jet lag.

Adult↗

PubMed2002

Nighttime changes in norepinephrine and melatonin content and serotonin turnover in pineal glands of young and old rats injected with Freund's adjuvant.

OBJECTIVES: This study was performed to search for changes in rat pineal function attributed to age and immunization with Freund's adjuvant. METHODS: Young (2 months) and old (18-20 months) Wistar rats were injected s.c. with Freund's adjuvant or its vehicle. Eighteen days later, at the acute phase of arthritis, pineal concentration of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE) and melatonin was measured by high pressure liquid chromatography at 4 different time intervals throughout the nocturnal activity span. RESULTS: Old rats had the lowest pineal 5-HT and 5-HIAA content, the decrease in 5-HIAA exceeding that of 5-HT; consequently, old rats had the lowest 5-HIAA/5-HT ratio, an index of pineal 5-HT turnover. Although immunization did not affect globally pineal 5-HT or 5-HIAA levels, significant interactions "immunization x age" and "immunization x time" were found, i.e., immunization augmented pineal 5-HT content at the beginning of the activity span in young rats and at second half of the activity span in young and old rats, and increased pineal 5-HIAA concentration in young rats at the second part of the activity span only. Freund's adjuvant treatment increased pineal 5-HT turnover exclusively in old rats, an effect mainly seen during the second part of the activity span. Old rats exhibited the lowest pineal NE and melatonin levels, immunization further depressing them. CONCLUSION: The effect of immunization with Freund's adjuvant on a number of pineal pre- and postsynaptic parameters are age-dependent.

Aging↗

PubMed2002

A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly.

OBJECTIVE: The present double blind-placebo controlled study was carried out to assess whether melatonin (3 mg p.o., fast release form) could be useful to reduce benzodiazepine dosage in old patients with minor sleep disturbance. The possible correlation of urinary excretion of 6-sulphatoxymelatonin (aMT6s) before starting treatment and outcome of treatment was also examined. METHODS: Forty-five patients (36 females, 70.5 +/- 13.1 years old) regularly taking anxiolytic benzodiazepines in low doses were studied. Overall quality of morning freshness, daily alertness, sleep quality, and sleep onset and offset time were assessed from structured clinical interviews and from logs completed by the patients. Patients were randomized to receive either melatonin or placebo for 6 weeks. On day 14 of treatment, benzodiazepine dose was reduced by half and on day 28, it was halted. No significant modifications of sleep or wakefulness were detected after benzodiazepine withdrawal. As compared to basal, there was a general lack of changes in quality of wakefulness or sleep in patients taking melatonin or placebo. Sleep quality of patients taking melatonin during the first two weeks of treatment was significantly lower than that of placebo. Melatonin advanced sleep onset by 27.9 +/- 11.9 min and decreased significantly the variability of sleep onset time (p= 0.03). The urinary concentration of aMT6s prior to the study did not correlate with any parameter examined. CONCLUSION: The present study does not support melatonin efficacy to reduce the use of benzodiazepines in low doses. This contrasted with the demonstrable effectiveness of melatonin to reduce benzodiazepine consumption in insomniac patients when used in hypnotic amounts.

Aged↗

PubMed2002

Melatonin in sleep disorders and jet-lag.

In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer's disease (AD) patients. Melatonin is effective to reduce significantly benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).

Aged↗

PubMed2002

The use of melatonin in Alzheimer's disease.

About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.

Aged↗

PubMed2002

Future of melatonin as a therapeutic agent.

Report of the round table conference summarizing the International Symposium on "Melatonin: Clinical Significance and Therapeutic Applications" is presented in this article. Some sleep disorders and circadian rhythm disturbances are the widely accepted indications for melatonin treatment. However, other possibilities for use of melatonin in the therapy should be also taken into account, including a co-treatment in cancer patients and free radical-related diseases. All aspects of the possible therapeutic use of melatonin as well as its safety, dosage, side effects and contraindications are discussed herein based on the round table conference and they are presented in this paper.

Animals↗

PubMedDate not supplied

Effect of ethanol on 24-hour hormonal changes in peripubertal male rats.

We analyzed the effect of chronic (4 weeks) ethanol feeding on 24-h variation of pituitary-testicular function in peripubertal male Wistar rats by measuring circulating concentrations of prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone, and thyrotropin. Animals were maintained under a 12-h light: 12-h dark photoperiod and received a liquid diet for 4 weeks, starting on day 35 of life. The ethanol-fed group received a diet similar to that provided to control animals, except that maltose was replaced isocalorically with ethanol. Ethanol replacement provided 36% of the total caloric content of the diet. Rats were killed at one of six times around the clock, beginning at zeitgeber time (ZT) 1 (ZT 0 = lights on). In ethanol-fed rats globally, secretion of prolactin was augmented, whereas secretion of follicle-stimulating hormone, luteinizing hormone, testosterone, and thyrotropin was decreased. Significant changes in the 24-h secretory pattern of circulating hormones occurred in rats receiving ethanol, including the appearance of two peaks (at ZT 1 and ZT 9), rather than one peak, of follicle-stimulating hormone during the inactive phase of the daily cycle, suppression of the maximum plasma luteinizing hormone concentration during the first part of the inactive phase, and appearance of a second peak of testosterone and prolactin during the second part of the inactive phase (at ZT 5 and ZT 9, respectively) and of a second peak of plasma thyrotropin during the first part of the active phase (at ZT 13). The significant positive correlation between testosterone and individual luteinizing hormone and prolactin concentrations in control animals was no longer observed after ethanol administration. Chronic ethanol administration presumably affects the endogenous clock that modulates the circadian variation of the pituitary-gonadal axis and thyrotropin release in growing male rats.

Age Factors↗

PubMedDate not supplied

Age-related changes in 24-hour rhythms of norepinephrine content and serotonin turnover in rat pineal gland: effect of melatonin treatment.

The 24-hour rhythms of pineal norepinephrine (NE) content and serotonin (5-HT) turnover [estimated from the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT] were studied in young (2 months) and aged (18-20 months) Wistar rats killed at 6 different time points throughout a 24-hour cycle. In the first study, significant changes dependent on the time of day were identified, with acrophases in the first half of the activity span for both parameters. Old rats showed significantly smaller mesor and amplitude of the 24-hour rhythm of pineal NE content. They also showed decreased amplitude of the pineal 5-HT turnover rhythm, in the absence of changes in mesor. In old rats, pineal 5-HT and 5-HIAA concentrations were 41-47% of those found in young rats. In a second study, young and old rats received daily intraperitoneal injections of melatonin (30 microg) or vehicle for 11 days at 19.00 h (i.e. 11 h after light on). Analyzed as a main factor in a factorial analysis of variance, both pineal NE content and 5-HT turnover decreased in old rats while pineal 5-HT turnover increased after melatonin treatment. Melatonin treatment augmented the amplitude of the 24-hour rhythm of pineal NE content by 120 and 52% in young and old rats, respectively. The amplitude of the 24-hour rhythm of pineal 5-HT turnover almost doubled after melatonin treatment in young rats and did not change in old rats. Melatonin injection did not modify the rhythm's acrophase. The results indicate that old rats had lower amplitude and lower mesor values of 24-hour variations in pineal NE content and 5-HT turnover. Melatonin treatment only partly restored pineal NE content and was devoid of activity on pineal 5-HT turnover and 5-HT and 5-HIAA concentration in old rats. Impairment of pineal melatonin synthesizing capacity and intrapineal responses to melatonin may underlie pineal aging in rats.

Aging↗

PubMedDate not supplied

Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum.

This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.

Aging↗

PubMedDate not supplied

Cerebroventricular administration of interferon-gamma modifies locomotor activity in the golden hamster.

The present study was undertaken to examine whether the intracerebroventricular (i.c.v.) administration of interferon (IFN)-gamma could modify 24-hour wheel running locomotor activity in the golden hamster. Hamsters implanted with a cannula in the third ventricle received a single i.c.v. injection of 1 microl of murine recombinant IFN-gamma (40 IU/microl) or its vehicle (saline) at ZT 6 or ZT 18 (with ZT 12 defined arbitrarily as the time of lights off) and their activities were monitored during 24 h. The i.c.v. administration of IFN-gamma at ZT 6 produced a significant phase advance in acrophase of rhythm, an effect not seen at ZT 18. Also, IFN-gamma depressed mesor value significantly, the effect was seen at both times. These results clearly showed that the circadian clock could be modified by IFN-gamma microinjections. One explanation could be the presence of IFN-gamma receptor in the rat suprachiasmatic nucleus, supporting a direct effect on the central oscillator. However, another hypothesis could not be ruled out.

Animals↗

PubMedDate not supplied

Circadian disorganization in experimental arthritis.

This review discusses the experimental evidence indicating that arthritis disrupts circadian organization, which was mainly derived from animal studies employing Freund's complete mycobacterial adjuvant (FCA). The defense response to antigenic challenge, mediated in part by cytokines, includes changes in chronobiological central nervous system function, like depressed daily activity, superficial sleep or anorexia. Interferon (IFN)-gamma receptors are detectable in the central circadian pacemaker, the hypothalamic suprachiasmatic nuclei, at a time when the capacity for photic entrainment of the pacemaker became established. The disruptive effects of the systemic injection of IFN on the circadian rhythms of locomotor activity, body temperature and clock-gene mRNA expression have been documented. In the last few years we have examined a number of immune and neuroendocrine circadian rhythms in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-hour organization of immune and neuroendocrine responses becomes altered. A hormonal pathway involving the circadian secretion of melatonin and a purely neural pathway including, as a motor leg, the autonomic nervous system innervating the lymph nodes were identified. The significant effects of the immune-mediated inflammatory response on the diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented the alteration in 24-hour rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin pretreatment prevented the alteration in the 24-hour variation in hypothalamic serotonin and dopamine turnover during the preclinical phase of Freund's adjuvant arthritis in rats. Some pinealectomy-induced immune changes in arthritic rats were also prevented by physiological concentrations of melatonin. Melatonin may play the role of an 'internal synchronizer' for the immune system.

Animals↗