bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of cervical sympathetic neurons on parathyroid hormone and calcitonin release in the rat: Independence of pineal mediation
Authors: Stern Javier E. , Esquifino Ana I. , Bonacho Manuel Garcia , Cardinali Daniel P
Published: February 2007

Stern JE, Esquifino AI, Bonacho MG, Cardinali DP. The influence of cervical sympathetic neurons on parathyroid hormone and calcitonin release in the rat: Independence of pineal mediation. J. Pineal Res. 1997; 22:9–15. © Munksgaard, Copenhagen

The objective of this study was to evaluate the involvement of the pineal gland in modulation of parathyroid hormone (PTH) and calcitonin release found in rats after changes in activity of cervical sympathetic nerves. The response of serum PTH to a hypocalcemia produced by EDTA injection, and of serum calcitonin to a hypercalcemia produced by administering calcium chloride, were studied in rats at the time of the wallerian degeneration of regional sympathetic nerves (i.e., 16 hr after superior cervical ganglionectomy, SCGx). Rats received a pinealectomy or its sham‐operation 4 days before SCGx. During wallerian degeneration of nerves after SCGx, a higher hypocalcemia and a lower PTH response were found as compared to sham‐SCGx rats, regardless of whether the pineal gland was present or not. When the response of calcitonin to a bolus injection of calcium chloride was assessed, rats subjected to SCGx 16 hr earlier showed a depressed calcitonin release, which was also unaffected after pinealectomy. To a similar extent in pinealectomized and sham‐pinealectomized rats, a mild stress given by the subcutaneous injection of turpentine oil brought about a greater hypocalcemia after EDTA, concomitantly with a higher PTH secretory response. In turpentine oil‐injected rats, the rise of serum calcitonin was significantly greater than that of vehicle‐treated rats, regardless of pineal presence. The results further indicate that cervical autonomic nerves constitute a pathway through which the brain modulates calcium homeostasis and do not support the participation of the pineal gland in short term changes of PTH or calcitonin release.
Potentially beneficial cardiovascular effects of melatonin administration in women
Authors: Cagnacci Angelo , Arangino Serenella , Angiolucci Marco , Maschio Elisabetta , Longu Giorgio , Metis Gian Benedetto
Published: February 2007

Cagnacci A, Arangino S, Angiolucci M, Maschio E, Longu G, Melis GB. Potentially beneficial cardiovascular effects of melatonin administration women. J. Pineal Res. 1997; 22:16–19. Munksgaard, Copenhagen

The cardiovascular effects induced by the daytime administration of melatonin (1 mg) were compared to those of placebo in 12 young women. In order to eliminate cardiovascular effects due to fluctuating endogenous sex steroids, all women were taking a fixed dose of monophasic contraceptive pill. In comparison to placebo, the administration of melatonin reduced, within 90 min, the pulsatility index of the internal carotid artery, evaluated by color Doppler ultrasound (P<0.01), as well as both systolic and diastolic blood pressure evaluated in supine position (P<0.01). Supine catecholamine levels were not significantly modified, but norepinephrine levels evaluated after 5 min of standing position were significantly reduced (P<0.02). These data suggest that in women the administration of 1 mg of melatonin may exert beneficial effects on blood vessels.
Histamine in the chick pineal gland: Origin, metabolism, and effects on the pineal function
Authors: Nowak Jerzy Z. , Zawilska Jolanta B. , Woldan‐Tambor Agata , Sçk Barbara , Voisin Pierre , Lintunen Minnamaija , Panula Pertti
Published: February 2007

Nowak JZ, Zawilska JB, Woldan‐Tambor A, Sçk B, Voisin P, Lintunen M, Panula P. Histamine in the chick pineal gland: Origin, metabolism, and effects on the pineal function. J Pineal Res. 1997; 22:26–32. © Munksgaard, Copenhagen

The chick pineal gland contains histamine andtele‐methylhistamine. The levels of both substances are elevated after treatment of chicks with the amino acid precursor of histamine, L‐histidine (1 g/kg, ip). In control and L‐histidine‐loaded animals the pineal levels of histamine andtele‐methylhistamine are higher in light‐exposed than in dark‐adapted animals (measured at the end of the light phase and in the middle of the dark phase of 12 hr light, 12 hr dark illumination cycle, respectively). The chick pineal gland contains histamine‐immunofluorescent cells displaying mast cell morphology; they are seen in the vicinity of the capsule and in the parenchyma. Enzymatic studies showed the presence of the activity of histamine synthesizing and inactivating enzyme, i.e., L‐histidine decarboxylase (HDC) and histamine‐methyltransferase (HMT). The detected enzyme activities were sensitive to specific inhibitors of HDC (α‐fluoromethylhistidine and α‐hydrazinohistidine) and HMT (quinacrine and metoprine); inhibitors of aromatic amino acid decarboxylase α‐methyl‐DOPA and NSD‐1015 were inactive on HDC. Exogenous histamine added to organ‐cultured chick pineals strongly stimulated endogenous cyclic AMP accumulation and moderately increased melatonin secretion. The data, considered collectively, suggest that in avians histamine, probably originating from the pineal mast cell compartment, may function as a regulator of pineal gland activity.
Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications
Authors: Yeleswaram Krishnaswamy , McLaughlin Lee G. , Knipe Jay O. , Schabdach David
Published: February 2007

Yeleswaram K, McLaughlin LG, Knipe JO, Schabdach D. Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications. J. Pineal Res. 1997; 22:45–51. © Munksgaard, Copenhagen

A review of the literature indicates that the absolute oral bioavailability of exogenous melatonin in humans or in preclinical animal models has not been adequately characterized; hence, this study was undertaken. Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration‐time curve. The apparent elimination half‐life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first‐pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose‐dependent bioavailability in dogs. In vitro permeability studies with CACO‐2 cells suggest that melatonin is likely to be well absorbed in humans. In vitro metabolism studies with fresh liver slices from rats as well as human donors were conducted to compare the initial rates of metabolism of melatonin between the two species and the results suggest that the intrinsic clearance of melatonin in humans may be lower than that in rats.
Effect of pinealectomy, superior cervical ganglionectomy, or melatonin treatment on 24‐hour rhythms in ornithine decarboxylase and tyrosine hydroxylase activities of rat spleen
Authors: Cardinali Daniel P. , Cutrera Rodolfo A. , Bonacho Manuel García , Esquifino Ana I.
Published: February 2007

ABSTRACT: Diurnal variations in splenic ornithine decarboxylase and tyrosine hydroxylase activities were examined in rats subjected to pinealectomy, bilateral superior cervical ganglionectomy, or their respective sham operations. Rats were treated with Freund's complete adjuvant or its vehicle 2 days before sacrifice. After immunization, splenic ornithine decarboxylase activity was augmented 5‐6‐fold. In both immunized and nonimmunized sham‐operated rats, significant diurnal variations in ornithine decarboxylase activity were detectable, with a maximum at early morning, acrophases after Cosinor analysis varying from 0845 to 1048h. In pinealectomized or superior cervical ganglionectomized, immunized rats, ornithine decarboxylase activity attained values 22‐27% lower than those of immunized sham‐operated controls, while amplitude decreased significantly by 27–30%. Administration of melatonin (30 μg/animal s.c. at late evening for 11 days in immunized rats) significantly augmented mesor levels of splenic ornithine decarboxylase activity and increased the amplitude of the diurnal rhythm both in pinealectomized and in superior cervical ganglionectomized rats. Melatonin treatment also augmented rhythm mesor in immunized, sham‐ganglionectomized rats, as well as rhythm amplitude in immunized and nonimmunized, sham‐ganglionectomized rats. Splenic tyrosine hydroxylase activity attained its maximum at late afternoon and early night, with acrophases varying from 1800 to 2023h. Immunization significantly increased mesor values of splenic tyrosine hydroxylase activity, whereas neither pinealectomy nor superior cervical ganglionectomy affected circadian rhythm parameters. Melatonin treatment augmented mesor values of tyrosine hydroxylase rhythm and increased its amplitude in pinealectomized, ganglionectomized, or sham‐operated rats. The results are compatible with the view that the pineal gland plays a role in circadian changes of immune responsiveness in rat spleen via an immunopotentiating effect of melatonin on splenic cell proliferation.
Protective effect of melatonin in carrageenan‐induced models of local inflammation: Relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity
Authors: Cuzzocrea Salvatore , Zingarelli Basilia , Gilad Eli , Hake Paul , Salzman Andrew L. , Szabó Csaba
Published: February 2007

Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabó C. Protective effect of melatonin in carrageenan‐induced models of local inflammation: Relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J. Pineal Res. 1997; 23:106–116. © Munksgaard, Copenhagen

In vitro studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. In the present study, we evaluated the effect of melatonin treatment in two models of acute inflammation (carrageenan‐induced paw edema and pleurisy), where oxyradicals, NO, and peroxynitrite play a crucial role in the inflammatory process. Our data show that melatonin (given at 62.5 and 125 μg/paw in the paw edema model or 25 and 50 mg/ kg in the pleurisy model) inhibits the inflammatory response (paw swelling, pleural exudate formation, mononuclear cell infiltration, and histological injury) in dose‐dependent manner in both models. Furthermore, our data suggest that melatonin exerts an inhibitory effect on the expression of the inducible isoform of NO synthase. Melatonin also prevented the formation of nitrotyrosine, an indicator of peroxynitrite, in both models of inflammation. Taken together, the present results demonstrate that melatonin exerts potent antiinflammatory effects. Part of these antiinflammatory effects may be related to an inhibition of the expression of the inducible NO synthase, while another part may be related to oxyradical and peroxynitrite scavenging.
Synchronization by low‐amplitude light‐dark cycles of 24‐hour pineal and plasma melatonin rhythms of hatchling European starlings (Sturnus vulgaris)
Authors: Gwinner E. , Zeman M. , Klaassen M.
Published: February 2007

Gwinner E, Zeman M, Klaassen M. Synchronization by low‐amplitude light‐dark cycles of 24‐hour pineal and plasma melatonin rhythms of hatchling European starlings (Sturnus vulgaris). J. Pineal Res. 1997; 23:176–181. © Munksgaard, Copenhagen

In young European starlings, as in other avian species, high‐amplitude 24‐hr rhythms in plasma and pineal melatonin are already present around the time of hatching. In chickens this rhythmicity results at least partly from the light sensitivity of the melatonin‐producing and ‐secreting system. In contrast to the chicken, the starling is a hole‐nesting bird, and it seemed questionable whether the low light intensities in the nest are sufficient to synchronize perinatal melatonin rhythms. We therefore exposed starling eggs to light cycles roughly simulating those measured in nest‐boxes, i.e., an 11‐hr phase of complete darkness and a 13‐hr phase consisting of 15 min of dim light (10 lux) alternating with 30 min of darkness. For one group the photophase lasted from 0600 to 1900 hr; for the other group the photophase lasted from 1800 to 0700 hr. In approximately 10‐hr‐old hatchlings of both groups, plasma and pineal melatonin concentrations were high during the dark phase and low during the light phase. We conclude that perinatal low‐amplitude light intensity changes of the kind experienced by hatching starlings in the field are sufficient for synchronizing the melatonin‐producing and ‐secreting system in the pineal and possibly other organs.
In vivo protection by melatonin against δ‐aminolevulinic acid‐induced oxidative damage and its antioxidant effect on the activity of haem enzymes
Authors: Princ Fernando G. , Maxit Andrea G. , Cardalda Carina , Batlle Alcira , Ana Juknat Adela
Published: February 2007

Princ FG, Maxit AG, Cardalda C, Batlle A, Juknat AA. In vivo protection by melatonin against δ‐aminolevulinic acid‐induced oxidative damage and its antioxidant effect on the activity of haem enzymes. J. Pineal Res. 1998; 24:1–8. © Munksgaard, Copenhagen

Accumulation of 8‐aminolevulinic acid (ALA), as it occurs in acute intermittent porphyria, is a potential endogenous source of reactive oxygen species (ROS) which can then produce oxidative damage to cell structures and macromolecules. This in vivo study investigated whether melatonin could prevent the deleterious effects of ALA. Rats were injected i.p. for 2 weeks with ALA (40 mg/kg on alternate days) and/or with melatonin (50 μg/kg or 500 μg/kg daily). Administration of pharmacological doses of melatonin reduced and/or prevented ALA‐induced lipid peroxidation (LPO) in both cerebral cortex and cerebellum, providing further evidence of melatonin's action as a ROS scavenger. Administration of pharmacological concentrations of melatonin to ALA‐injected rats showed the protective properties of melatonin on the activities of both porphobilinogen‐deaminase and δ‐aminolevulinate dehydratase (ALA‐D) in the cerebral cortex; the effect on ALA‐D activity was unexpectedly high (at least 6‐fold), indicating that, besides acting as a scavenger of hydroxyl radicals, melatonin may exert its protection on ALA‐D through other mechanisms, such as increasing mRNA levels of antioxidant enzymes or/ and inducing glutathione peroxidase activity. The possibility that changes in the expression of antioxidant enzymes could affect the expression of other proteins, even those not related to the cellular ROS homeostasis, should also not be discarded. The potential use of melatonin as an antioxidant and for its reactivating properties in the treatment of acute porphyrias is considered.
Localization and quantification of melatonin receptors in the diencephalon and posterior telencephalon of the sheep brain
Authors: Chabot V. , Caldani M. , de Reviers M.M. , Pelletier J.
Published: February 2007

Chabot V, Caldani M, de Reviers MM, Pelletier J. Localization and quantification of melatonin receptors in the diencephalon and posterior telencephalon of the sheep brain. J. Pineal Res. 1998; 24:50–57. © Munksgaard, Copenhagen

In an attempt to better understand the mechanisms by which melatonin controls neuroendocrine activity, we tried to define with accuracy the brain areas where the density of melatonin receptors is the highest in sheep and to establish their characteristics. The specific labelling of 125I‐melatonin was first revealed by autoradiography on brain sections of the posterior telencephalon and diencephalon in three ewes. The extent and position of the five structures where the binding was found to be the highest (i.e., the pars verticalis and pars horizontalis of the nucleus tractus diagonalis, the septal area, the bed nucleus of the stria terminalis, and the ventromedial hypothalamic area) were then accurately defined by image analysis. In comparison to the landmarks given by image analysis, photographs of coronal sections of another ewe permitted the accurate definition of the limits of the structures to be punched in a second step. In six ewes, each of the five structures previously identified were punched from frozen coronal sections and binding of 125I‐melatonin to membrane preparations was studied individually by Scatchard analysis. The correlation coefficient between the B/F ratio and binding (B) was in the range of 0.96–0.98, indicating that a precise quantification was possible in these different structures. The Bmax was the highest in the bed nucleus of the stria terminalis, the septal area, and the ventromedial hypothalamic area (1.38, 1.25, and 0.95 fmol/mg protein, respectively). All Kd values were less than 10 pM and the Hill coefficient was close to 1, indicating the presence of a single class of receptor to 125I‐melatonin. These results indicate the reliability of a method used to measure with accuracy low concentrations of melatonin receptors in brain structures. In addition, the ventromedial hypothalamic area was found to be rich in melatonin receptors. This region is known to be involved in the central gonadotrope control in sheep.
Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs
Authors: Bubenik G.A. , Ayles H.L , Friendship R.M. , Brown G.M. , Ball R.O.
Published: February 2007

Bubenik GA, Ayles HL, Friendship RM, Brown GM, and Ball RO. Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs. J. Pineal Res. 1998; 24:62–66. © Munksgaard, Copenhagen

Four weeks of administration of melatonin mixed in the diet (5 mg/kg of food) significantly reduced the incidence of gastric ulcers in young pigs. In control and melatonin supplemented animals, significantly higher levels of melatonin were found in the stomach tissues as compared to jejunum, ileum, or colon. Pigs with the most severe ulcers exhibited significantly lower concentrations of melatonin in their stomach tissue and the blood plasma. Pigs fed coarsely ground diet exhibited higher tissue levels of melatonin in the stomach than animals fed a finely ground diet. Coarse diet was also associated with a lower score of gastric ulcers. No relationship between tissue levels of melatonin and the severity of gastric ulcers was found in other segments of the gastrointestinal tract. In the second experiment we determined that there was no significant difference between the gastro‐protective effects of 2.5, 5.0, and 10.0 mg of melatonin mixed per 1 kg of food. A coarsely ground diet is hypothesized to have a gastro‐protective effect by stimulating the production of melatonin in the stomach tissues. Dietary supplementation of food with melatonin, at threshold levels perhaps lower than 2.5 mg/kg/feed, may significantly reduce the incidence of gastric ulcers in pigs.
RETRACTED: Protective effect of melatonin in a non‐septic shock model induced by zymosan in the rat
Authors: Cuzzocrea Salvatore , Zingarelli Basilia , Costantino Giuseppina , Caputi Achille R
Published: February 2007

ABSTRACT: In vitro studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. Recently, it has been proposed that zymosan, a non‐bacterial agent, causes inflammation by inducing the production of various cytokines and pro‐inflammatory mediators. In the present study we evaluated the effect of melatonin treatment in a non‐septic shock model induced by zymosan in the rat. Administration of zymosan (500 mg/kg intraperitoneally) in the rat induced acute peritonitis, as assessed by a marked increase in the leukocyte count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. This inflammatory process coincided with the damage of lung, small intestine, and liver, as assessed by histological examination and by increase of myeloperoxidase activity, indicative of neutrophil infiltration.

Peritoneal administration of zymosan in the rat induced also an significant increase in the plasma levels of nitrite and nitrate, stable metabolites of nitric oxide (NO), and in the levels of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, at 18 hr after zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific “footprint” of peroxynitrite, in the lung of zymosan‐shocked rats. Pretreatment of zymosan‐shocked rats with melatonin (25 and 50 mg/kg, intraperitoneally, 5 min before zymosan) prevented in a dose dependent manner the development of peritonitis and reduced peroxynitrite formation. In addition, melatonin (50 mg/kg, intraperitoneally, 5 min before zymosan) was effective in preventing the development of organ failure since tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, was reduced in lung, small intestine, and liver. Taken together, the present results demonstrate that melatonin exerts potent antiinflammatory effects.
Structure of the ovine pineal gland during prenatal development
Authors: Regodón Sergio , Franco Antonio , Masot Javier , Redondo Eloy
Published: February 2007

Regodón S, Franco A, Masot J, Redondo E. Structure of the ovine pineal gland during prenatal development. J. Pineal Res. 1998; 25:229–239. © Munksgaard, Copenhagen

The structure of the pineal gland of 32 clinically healthy ovine embryos at different stages of development was studied. Embryos were arranged in four age groups, each containing eight embryos (four males and four females), defined in terms of the most relevant histological features: group 1 (27 to 69 days of prenatal development), group 2 (70 to 97 days), group 3 (98 to 116 days), and group 4 (117 to 150 days). At around 30 days of prenatal life, according to topographic criteria, the pineal outline begins to differentiate into a dorsal evagination of the diencephalic medium line, close to the anterior and posterior commissures. The growth of the pineal is biphasic. The ontogenic‐proliferative phase begins at 30 days and includes the invasion of ependymal cells and the proliferation of the pineal parenchyma cells. The hypertrophic‐differentiation phase includes the volume increment of the pinealoblasts and their differentiation into pinealocytes; this occurs at around 118 days. At around 98 days, the gland acquires its definitive compact appearance due to 1) glandular growth in constant volume and 2) the obliteration of pineal recess. The glandular structure displays a parenchyma made up of pinealoblasts, interstitial cells, and cells containing pigment. The pineal stroma is structured in pseudolobes formed by reticular and collagen fiber septae, which constitute together the interstitial cell prolongation net, which is the support structure of the whole glandular cytology. Capillaries are detected all over the glandular surface, being more abundant in the medullary zone. At around 98 days of prenatal development, VIP (Vasoactive Intestinal Peptide) positive fibers, distributed around blood vessels and among pinealoblasts were detected.
Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions
Authors: Messner M. , Hardeland R. , Rodenbeck A. , Huether G.
Published: February 2007

Messner M, Hardeland R, Rodenbeck A, Huether G. Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions. J. Pineal Res. 1998; 25:251–259. © Munksgaard, Copenhagen

The fate and disposition of the melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after a single and often a very large dose of labelled melatonin. In continuous infusion experiments in freely moving rats, we have recently demonstrated that considerable amounts of melatonin must be endogenously released in order to achieve and maintain approximately a 10‐fold elevation of the low daytime plasma levels of this hormone. We have now applied this infusion paradigm to study the fate and tissue accumulation of [3H]‐melatonin continuously infused under near physiological conditions into the jugular vein for a period of 2 hr. The retention of [3H]‐melatonin and chloroform‐insoluble [3H]‐melatonin‐metabolites was measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and 6 hr later. At the end of the 2 hr infusion period, about 45% of the administered melatonin was recovered as water‐soluble metabolites in the urine and about 20% in the small intestine. Some accumulation of [3H]‐melatonin‐derived water‐soluble radioactivity was also noticed in the liver, colon, adrenals, and pituitary, as well as in the feces. The subcellular distribution of this radioactivity differed between tissues. During the period of 6 hr after the termination of infusion, a considerable amount of melatonin‐derived radioactivity was found to become increasingly attached to the proteous interlayer of chloroform extracts of tissues and subcellular fractions, from where it could only be liberated by protease treatment.
Monozygotic twins with Alzheimer's disease treated with melatonin: Case report
Authors: Brusco Luis I. , Márquez Miguel , Cardinali Daniel P.
Published: February 2007

Brusco LI, Márquez M, Cardinali D.P. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report. J. Pineal Res. 1998; 25:260–263. © Munksgaard, Copenhagen

Monozygotic twins with Alzheimer's disease of 8 years duration were studied. The onset of the disease differed by about 6 months between twins and was characterized by a primary impairment of memory function. Clinical evaluation at the time of diagnosis indicated a similar cognitive and neuroimaging alteration in both patients, as well as a similar neuropsychologic impairment. A possible genetic origin of the disease was suggested by a similar disease suffered by the mother. Patients were initially treated with vitamin E (800 I.U./day). Starting at approximately the same time (about 3 years ago), they received 50 mg/day thioridazine because of the behavioral and sleep disorder. One of the patients was treated with melatonin (6 mg orally) at bed time daily for 36 months. Evolution of the disease in the melatonin‐treated patient indicated a milder impairment of memory function, with substantial improvement of sleep quality and reduction of sundowning. This led to discontinuance (after 3 months) of thioridazine treatment. Present clinical evaluation indicated a difference in functional stage of the disease between the twins (Functional Assessment Tool For Alzheimer's Disease, FAST), with a score of 5 in the twin who received melatonin and of 7b in the twin who did not receive it. Since experimental data on melatonin in animals indicated its antioxidant, antiapoptotic, and β‐amyloid‐decreasing activity, the hypothesis that melatonin has a beneficial effect in Alzheimer's disease patients should be considered.
Pineal opioid receptors and analgesic action of melatonin
Authors: Ebadi Manuchair , Govitrapong Piyarat , Phansuwan‐Pujitu Pansiri , Nelson Francine , Reiter Russel J.
Published: February 2007

Abstract:Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In most species, including the humans, the circulating levels of melatonin, a substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at night, pinealectomy abolishes the analgesic effects of melatonin, and mu opioid receptor antagonists disrupt the day‐night rhythm of nociception. It is believed that melatonin, with its sedative and analgesic effects, is capable of providing a pain free sleep so that the body may recuperate and restore itself to function again at its peak capacity. Moreover, in conditions when pain is associated with extensive tissue injury, melatonin's ability to scavenge free radicals and abort oxidative stress is yet another beneficial effect to be realized. Since melatonin may behave as a mixed opioid receptor agonist‐antagonist, it is doubtful that a physician simply could potentiate the analgesic efficacy of narcotics such as morphine by coadministering melatonin. Therefore, future research may synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.
Prediction of nocturnal plasma melatonin from morning urinary measures
Authors: Graham Charles , Cook Mary R. , Kavet Robert , Sastre Antonio , Smith Deborah K.
Published: February 2007

Abstract: A growing literature indicates that blood levels of the hormone melatonin may have important implications for human health and wellbeing. Melatonin is synthesized and released into the general circulation at night, however, and it is seldom feasible to draw blood samples at night in epidemiological studies. There is some evidence that levels of urinary melatonin and of 6‐sulfatoxymelatonin (aMT6s), the major metabolite of melatonin, accurately reflect nocturnal plasma melatonin. If this is the case, urinary assays could be powerful tools for epidemiological studies. A laboratory‐based study was performed to examine the relationships between nocturnal plasma melatonin, morning urinary melatonin, and morning urinary aMT6s levels in 78 men. The relationship between total nocturnal plasma melatonin and both urinary aMT6s corrected for creatinine and urinary melatonin is significant. Combining the two urinary measures accounts for 72% of the variance in total plasma melatonin. Peak nocturnal plasma melatonin also was significantly related to urinary melatonin and to aMT6s. The urinary measures show good sensitivity and specificity in identifying individual differences in nocturnal plasma melatonin levels. These results support the inclusion of morning urine samples to assess the contribution of the hormone melatonin in occupational or residential studies involving healthy, young men.
Changes with age in daytime and nighttime contents of melatonin, indoleamines, and catecholamines in the pineal gland: A comparative study in rat and Syrian hamster
Authors: Míguez J. M. , Recio J. , Sánchez‐Barceló E. , Aldegunde M.
Published: February 2007

Abstract: Previous studies in rodents showed a severe deterioration of pineal physiology with aging. The present study investigated the age‐related changes in the content of monoamines and metabolites in rat and Syrian hamster pineal gland. In addition to melatonin, the levels of 5‐hydroxytryptophan (5HTP), serotonin (5HT), 5‐hydroxyindoleacetic acid (5HIAA), N‐acetylserotonin (N‐Ac‐5HT), dopamine (DA), 3,4‐dihydroxyphenylacetic acid (DOPAC), and noradrenaline (NA) were measured by HPLC. Pronounced reductions were found in 5HT and 5HIAA contents during daytime in rats of 24 months, which had not been observed in animals of 12 months. In addition, nighttime pineal 5HIAA, N‐Ac‐5HT, and melatonin contents were decreased in the old rats, although a significant day: night variation persisted. Also a diurnal fluctuation in NA, DA, and DOPAC contents was present in young and middle‐aged rats but not for NA and DOPAC in the oldest rats due to a decrease in the nighttime levels. Pineal DA levels were also reduced in 24‐month‐old rats during the night, although a marked day: night change was still found. In the Syrian hamster pineal, significant reductions in daytime 5HT and 5HIAA were found respectively at 12 and 18 months, while nighttime levels of these compounds were decreased from 18 months. The nocturnal content of N‐Ac‐5HT dropped gradually from 12 months, and melatonin was reduced by 74% and 86% in hamsters of 18 and 24 months, respectively. In all these compounds, a significant day: night variation was observed irrespective of age. However, neither a day: night variation nor an effect of aging was found in terms of pineal NA content. In contrast, pineal DA and DOPAC levels displayed a diurnal variation in hamsters of 1.5 and 6 months, but not in animals of 12 and 18 months due a reduced nighttime content. These data suggest that the decline of pineal melatonin with age is a consequence of a deficit in the pathway of serotonin utilization. This probably is explained by a reduced N‐acetyltransferase activity, which may be linked to impaired pineal catecholaminergic neurotransmission.
Maternal‐fetal transfer of melatonin in pregnant women near term
Authors: Okatani Yuji , Okamoto Keiichi , Hayashi Kazutoshi , Wakatsuki Akihiko , Tamura Seiichiro , Sagara Yusuke
Published: February 2007

Abstract: Our objective was to evaluate the maternal‐fetal transfer of melatonin in pregnant women. Serum melatonin concentration was measured by high‐performance liquid chromatography with electrochemical detection in a maternal vein and in the umbilical artery and umbilical vein at the time of birth. Blood samples were obtained from 12 women who had spontaneously delivered vaginally at night. A single oral dose of melatonin was administered to each of 33 patients who underwent a cesarean section, and. blood samples were taken at 1,2, 3, or 4 hr after the administration of melatonin at delivery. Cesarean section was performed between 1300 and 1500 hr. The mean melatonin concentrations of melatonin in maternal peripheral venous blood and umbilical arterial and umbilical venous blood did not differ significantly, and positive correlations in the serum levels of melatonin were observed between the three sources of blood. The oral administration of 3 mg of melatonin to pregnant women led to marked increases in the serum levels of melatonin, with maximum levels observed 2 hr (21.84 ± 2.09 ng/ml) after drug administration. Changes in serum levels of melatonin in the umbilical vein and artery resembled those found in the maternal vein. Serum melatonin concentrations did not differ significantly between the maternal vein and the umbilical veins. Serum levels of melatonin in the umbilical vein after the administration of melatonin were significantly and closely correlated with those in the maternal vein (r = 0.924, (P < 0.001). These results suggest that, in humans, melatonin is transferred from the maternal to the fetal circulation both easily and rapidly. A potential for the therapeutic use of melatonin as an antioxidant exists in the patients with preeclampsia.
Neuroendocrine, immunohistochemical, and ultrastructural study of pineal region tumors
Authors: Grimoldi Nadia , Tomei Giustino , Stankov Bojidar , Lucini Valeria , Masini Battistina , Caputo Valentina , Repetti M. Luisa , Lazzarini Giulia , Gaini S. M. , Lucarini Claudio , Fraschini Franco , Villani Roberto
Published: February 2007

Abstract: Thirteen patients with tumors in the pineal region were submitted to pre‐ and post‐operative blood sampling (08:00, 14:00, 20:00, and 02:00 hr) for three or four consecutive days. A single cerebrospinal fluid (CSF) sample was collected at surgery, and melatonin levels determined. In all patients, serum and CSF beta subunit of human chorionic gonadotrophin (βHCG), carcino embryonic antigen (CEA), and alpha‐fetoprotein (AFP) levels were measured. Histology revealed four pineocytomas, one pineoblastoma, four germinomas, one immature teratoma, one pilocytic astrocytoma, one lymphoma, and one meningioma. Serum and CSF levels of serological biomarkers were normal, except for one of the germinoma cases. In most patients, alteration either in the circadian rhythm or in the melatonin concentration was observed before surgery. In benign neoplasms the circadian rhythm was conserved. In pineoblastoma, lymphoma, and three out of four germinomas, melatonin concentrations were undetectable. In one case of germinoma, melatonin levels were high, with the circadian rhythm being abolished. According to conventional histology, all germinomas were similar. Therefore, in a rare case of pineal germinoma with high melatonin levels, the tissue was subjected to an in depth investigation (immunohistochemical and ultrastructural) in order to determine the pathology and the possible differences from the other typical germinomas. Results were compared to those provided from other pineal neoplasms. Electron microscopy examination detected the presence of clusters of intermediate filaments and numerous electrondense granules only in the case of a germinoma producing melatonin.
Perinatal development of circadian melatonin production in domestic chicks
Authors: Zeman M. , Gwinner E. , Herichová I. , Lamošová D. , Košt'ál L.
Published: February 2007

Abstract: In contrast to the situation in mammals, in which circadian melatonin production by the pineal gland does not begin until some time after birth, the development of pineal gland rhythmicity is an embryonic event in the precocial domestic fowl. A distinct melatonin rhythm was found in 19‐d‐old chick embryos maintained under light:dark (LD) 16:8. No significant variation in melatonin levels was detected in embryos exposed to LD 8:16. The melatonin rhythm in the pineal gland and plasma of chick embryos incubated for 18 d in LD 12:12 persisted for 2 d in constant darkness indicating that melatonin production is under circadian control at least from the end of embryonic life. A I‐d exposure to a LD cycle during the first postembryonic day was sufficient to entrain the melatonin rhythm, and previous embryonic exposure to either LD or constant darkness (DD) neither modified this rapid synchronization nor did it affect the melatonin pattern during the two subsequent days in DD. It is suggested that, in contrast to the situation in mammals, the avian embryo has evolved its own early circadian melatonin‐producing system because, as a consequence of its extrauterine development, it cannot use the system of its mother.
Melatonin receptors in neonatal pig brain and pituitary gland
Authors: Williams L. M. , Hannah L. T. , Bassett J. M.
Published: February 2007

Abstract: Summer infertility remains a major problem in domestic pigs. It has been proposed that sows which display this trait are inherent seasonal breeders. The influence of photoperiod on domestic pigs has been difficult to ascertain as significant diurnal fluctuations in blood levels of the pineal hormone, melatonin, which provide a direct neuroendocrine transduction of the ambient photoperiod in other species, remain questionable in adult pigs. To investigate whether the pig is potentially receptive to melatonin, central sites of action for this hormone were localized and characterized within the brain and pituitary of the neonatal pig by in vitro autoradiography using 2‐(125I)iodomelatonin. Specific binding was distributed over a number of discrete regions of the brain including the cerebral cortex, hypothalamus, thalamus, brainstem, and cerebellum. The choroid plexus, and the pars tuberalis and pars distalis of the pituitary were also specifically labeled. Specific binding was completely abolished in the presence of 10−7 M melatonin, and inhibited in the presence of 10 −4 M GTPγS (guanosine‐5‐0‐(3‐thiotriphosphate)), a non‐hydrolysable analogue of GTP, in all regions examined, indicating that binding is representative of a G‐protein coupled receptor.

Characterization studies showed that 2‐(125I)iodomelatonin binding was saturable with a dissociation constant (Kd) in the low picomolar range (∼ 30 pM). Competition studies with iodomelatonin, melatonin, N‐acetylserotonin and serotonin (5‐HT) gave IC50 values similar to those previously characterized for the melatonin receptor in the ovine pars tuberalis.
Zinc accumulation in adriamycin‐induced cardiomyopathy in rats: Effects of melatonin, a cardioprotective antioxidant
Authors: Morishima Itsuro , Okumura Kenji , Matsui Hideo , Kaneko Shinji , Numaguchi Yasushi , Kawakami Kei , Mokuno Shinji , Hayakawa Makoto , Toki Yukio , Ito Takayuki , Hayakawa Tetsuo
Published: February 2007

Abstract: We have recently reported that melatonin protects against adriamycin‐induced cardiomyopathy whose pathogenesis may involve free radicals and lipid peroxidation. Melatonin has also been shown to affect zinc turnover. Since zinc may act as an antioxidant, we investigated the role of zinc in the pathogenesis of adriamycin‐induced cardiomyopathy as well as in the treatment of melatonin against this disorder. Sprague Dawley rats were given adriamycin (cumulative dose, 15 mg/kg); melatonin (cumulative dose, 84 mg/kg); adriamycin plus melatonin; adriamycin plus probucol, another antioxidant (cumulative dose, 90 mg/kg); or vehicle alone, according to previously‐used regimens. Cardioprotective effects of both antioxidants (melatonin and probucol) were confirmed by the parameters of fractional shortening, heart weight, heart/body weight ratio, ascites volume, and mortality. Adriamycin increased both the myocardial and plasma levels of thiobarbituric acid reactive substances (TBARS) and myocardial zinc levels, and decreased plasma zinc levels. The significant negative correlation observed between the myocardial and plasma zinc levels (r =0.73, P < 0.01) among the samples of adriamycin‐treated and control rats suggested an internal redistribution of zinc. Melatonin and probucol were equally effective in inhibiting the increase in myocardial TBARS as well as zinc levels, suggesting that myocardial zinc accumulation might be a protective response against adriamycin‐induced oxidative stress. Melatonin also inhibited the adriainycin‐induced decrease in plasma zinc levels; probucol was not as effective in doing so. In addition to melatonin's antioxidative effect, it may have the effect of maintaining the plasma zinc levels.
Presence and effects of melatonin in Trypanosoma cruzi
Authors: Macias M. , Rodrigueez‐Cabezas M. N. , Reiter R. J. , Osuna A. , Acuña‐Castrovejo D.
Published: February 2007

Abstract: The unicellular organism Trypanosoma cruzi is an eukaryote whose cell cycle mainly occurs under darkness in the insect gut. The unique external phase corresponds to the metacyclic forms, the forms that are able to infect humans, which appear within the insect deyections. Thus, light may be a powerful stressor in this unicell. Epimastigote forms (the parasite forms that grow and transform to metacyclic forms in the insect gut) of Trypanosoma cruzi grow normally when cultured in a LD cycle of 0:24 hr, reaching exponential growth by the 7th day. A pulse of 2 hr of light (LD 2:22) was enough to block the growth of the epimastigotes, an effect that was correlated with the expression of heat‐shock proteins during the first 120 min of light exposure. Thereafter, protein synthesis decreased. Light exposure of metacyclic forms also inhibits the parasitization ability. It is known that light regulates the production of melatonin in most animal species studied, including other unicells such as dinoflagellates. T. cruzi contains and synthesizes melatonin and, thus, light‐mediated events on the parasite biological cycle could be mediated by light‐induced changes in melatonin produced by this unicell. Epimastigotes cultured under continuous darkness produce melatonin over the 24 hr period in a biphasic manner. Coinciding with the melatonin peaks, there was high melatonin efflux from the parasite into the medium. Epimastigotes cultured for 7 days under a LD cycle of 2:22 hr showed a 55% reduction in melatonin content, although this reduction seems not to be related with the growth delay. In fact, incubation of epimastigotes with exogenous melatonin (1 pM) did not affect parasite growth, but significantly reduced their transformation into metacyclic forms by the 7–8th day of treatment. Thus, the light‐dependent decrease in melatonin production by the unicell may be responsible, at least partially, for the light‐induce parasitization inhibition. Moreover, melatonin production is highest in the metacyclic forms. These data support a link between light, melatonin production and parasitization ability of T. cruzi and suggest the participation of the indoleamine in its biological cycle.
Melatonin protects human red blood cells from oxidative hemolysis: New insights into the radical‐scavenging activity
Authors: Tesoriere L. , D'Arpa D. , Conti S. , Giaccone V. , Pintaudi A. M. , Livrea M. A.
Published: February 2007

Abstract: Antioxidant activity of melatonin in human erythrocytes, exposed to oxidative stress by cumene hydroperoxide (cumOOH), was investigated. CumOOH at 300 μM progressively oxidized a 1% suspension of red blood cells (RBCs), leading to 100% hemolysis in 180 min. Malondialdehyde and protein carbonyls in the membrane showed a progressive increase, as a result of the oxidative damage to membrane lipids and proteins, reaching peak values after 30 and 40 min, respectively. The membrane antioxidant vitamin E and the cytosolic reduced glutathione (GSH) were totally depleted in 20 min. As a consequence of the irreversible oxidative damage to hemoglobin (Hb), hemin accumulated into the RBC membrane during 40 min. Sodium dodecyl sulfate (SDS) gel electrophoresis of membrane proteins showed a progressive loss of the cytoskeleton proteins and formation of low molecular weight bands and protein aggregates, with an increment of the intensity of the Hb band. Melatonin at 50 μM strongly enhanced the RBC resistance to oxidative lysis, leading to a 100% hemolysis in 330 min. Melatonin had no effect on the membrane lipid peroxidation, nor prevented the consumption of glutathione (GSH) or vitamin E. However, it completely inhibited the formation of membrane protein carbonyls for 20 min and hemin precipitation for 10 min. The electrophoretic pattern provided further evidence that melatonin delayed modifications to the membrane proteins and to Hb. In addition, RBCs incubated for 15 min with 300 μM cumOOH in the presence of 50 μM melatonin were less susceptible, when submitted to osmotic lysis, than cells incubated in its absence. Extraction and high‐performance liquid chromatography (HPLC) analysis showed a much more rapid consumption of melatonin during the first 10 min of incubation, then melatonin slowly decreased up to 30 min and remained stable thereafter. Equilibrium partition experiments showed that 15% of the melatonin in the incubation mixture was recovered in the RBC cytosol, and no melatonin was extracted from RBC membrane. However, 35% of the added melatonin was consumed during RBC oxidation. Hydroxyl radical trapping agents, such as dimethylsulfoxide or mannitol, added into the assay in a 1,000 times molar excess, did not vary melatonin consumption, suggesting that hydroxyl radicals were not involved in the indole consumption. Our results indicate that melatonin is actively taken up into crythrocytes under oxidative stress, and is consumed in the defence of the cell, delaying Hb denaturation and release of hemin. RBCs are highly exposed to oxygen and can be a site for radical formation, under pathological conditions, which results in their destruction. A protective role of melatonin should be explored in hemolytic diseases.