bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of somatostatin in rat pineal cells in culture
Authors: Mato E. , Santisteban P. , Viader M. , Capellá G. , Fornas O. , Puig‐Domingo M. , Webb S.M.
Published: February 2007

Abstract: The expression of somatostatin mRNA was investigated in rat pineal cells after 1 week in culture, using reverse transcription of mRNA into cDNA and the polymerase chain reaction. The positive expression in cultured pineal cells demonstrates the capacity of this gland to synthesize somatostatin in denervated cells. Thus, apart from the neural origin of pineal somatostatin, which has been described in detail in the bovine species, a parenchymal source is demonstrated.
Reliable analysis of individual human megaton profiles by complex cosinor analysis
Authors: Lerchl Alexander , Partsch Carl‐Joachim
Published: February 2007

Lerchl A, Partsch C‐J. Reliable analysis of individual human melatonin profiles by complex cosinor analysis. J. Pineal Res. 1994: 16: 85–90.

The analysis of diurnal secretion patterns of the pineal hormone melatonin should provide information about magnitude of peak concentration, time of peak (acrophase), and duration of elevated hormone levels. We report here on a method for analysis of human melatonin secretary rhythms which fulfills these requirements with considerable precision. Blood samples were obtained from 10 healthy male volunteers at 30 min intervals throughout a 24 hr period, three times (the initial blood sampling was repeated after 2 weeks and 3 months). These sets of 48 plasma samples per volunteer were analyzed for melatonin by radio immunoassay. The mean intra‐assay variation was 10. 3%, and inter‐assay variations were 15. 8% at 21 pg/ml, 11% at 28 pg/ml, and 9. 4% at 48. 6 pg/ml. Data were subjected to single cosinor analysis (SCA) or analyzed by a complex cosinor analysis (CCA) with the fundamental and the first harmonic as parameters. Both methods provided essentially the same information about the macrophages, whereas the CCA had a clear advantage in terms of better regression coefficients between the original data points and the calculated curve (CCA: r = 0.952 ± 0.018; SCA: r = 0.867 ± 0.039 [means ± SD]; P < 0.001). As a consequence, maximum and minimum values and the times of onset and cessation of melatonin production could be estimated easily and reliably without the need for rough and/or subjective measures. By comparing the three sampling sessions, the secretary rhythm of each individual was clearly reproducible (mean coefficient of variation 8. 4%), thus confirming earlier work. Interindividual differences, however, were quite pronounced, especially with respect to amplitudes (more than 25% coefficient of variation). The present method for describing the secretary pattern of emblazoning may also be useful for other study protocols since it requires only slightly more effort than the commonly used single cosinor analysis.
Photoperiod and melatonin affect testicular growth in the marsh rice rat (Oryzomys palustris)
Authors: Edmonds Kent E. , Stetson Milton H.
Published: February 2007

Edmonds KE, Stetson MH. Photoperiod and melatonin affect testicular growth in the marsh rice rat (Orgzonys palustris). J. Pineal Res. 1994: 17: 86–93. ©Munksgaard 1994

Reproduction in rice rats is subject to photoperiodic control and the pineal gland mediates this effect. We examined the effects of the pineal gland hormone melatonin on testicular weight when administered via implants, injections, and infusions. Testicular weight was modified by photoperiod and the size of the melatonin implant. Twenty‐millimeter implants suppressed testicular weight in rice rats housed on 12‐ and 16‐hr photoperiods, while those housed on a 14‐hr photoperiod were more sensitive to melatonin; in these animals 10‐ and 20‐mm implants inhibited testicular weight. Melatonin implants also prevented rice rats from responding to a change in photoperiod with the appropriate alteration of testicular growth. Melatonin injections inhibited testicular growth when administered before lights out on LD 14: 10, but not on LD 16: 8. Morning injections had no effect on either photoperiod. Finally, 12‐hr duration melatonin infusions inhibited testicular growth in pinealectomized rice rats on LD 16: 8, while 6‐hr duration infusions were without effect. These data show that the pineal, through the secretion of melatonin, is a phototransducing organ intimately involved in testicular growth in rice rats.
Are the annual reproductive and body weight rhythms in the male European hamster (Cricetus cricetus) dependent upon a photoperiodically entrained circannual clock?
Authors: Masson‐Pévet M. , Naimi F. , Canguilhem B. , Saboureau M. , Bonn D. , Pevet P.
Published: February 2007

Masson‐Pévet M, Naimi F, Canguilhem B, Saboureau M, Bonn D, Pévet P. Are the annual reproductive and body weight rhythms in the male European hamster (Cricetus cricetus) dependent upon a photoperodically entrained circannual clock? J. Pineal Res. 1994; 17:151–163.

Most or the data obtained so far on the European hamster (Cricetus cricetus) suggest direct photoperiodically driven seasonal changes in sexual activity and body weight. The results of the present long‐term study support the hypothesis that these annual changes are the expression of photoperiodically driven endogenous circannual rhythms. When subjected following capture (April‐May) to constant conditions of long photoperiod (LP) and constant temperature a large number of the European hamsters present, in September‐December, complete gonadal atrophy associated with a decrease in body weight. A sexual reactivation as well as an increase in body weight are observed in the same animals between January and April. Of the six animals that survived long enough, two only presented partial gonadal atrophy during the second year. These observations clearly demonstrate that the decline in sexual activity in subjective autumn does not require a decrease in photoperiod, at least in the first year. Theoretically, the observed rhythms, if circannual in nature, would be generated by a self‐sustained annual oscillator (circannual clock) able to function in the absence of a photoperiodic input. Pinealectomy makes animals unable to detect or measure photoperiodic information. Of the six European hamsters tested (pinealectomized in June and then kept continuously under LP), five showed clear annual rhythms in body weight and reproductive capacities for two consecutive years. Clearly endogenous annual rhythms were expressed in these conditions. To be entrained to a 1‐year period, such a circannual clock should, however, be able to react to either LP and/or to short‐photoperiod (SP), at least at certain periods of the annual cycle. In animals exposed to LP in August or October, after gondal atrophy had been established by exposure to natural SP, gonadal regrowth started in December or January, about 2 to 3 months earlier than in animals kept outside or in experimental SP. With the same experimental conditions, exactly the same results were obtained in pinealectomized animals; thus stimulatory effect of LP or LP‐induced phase advance of the circannual clock can be excluded. The absence of the SP information would then induce such reaction. In animals kept under constant LP and temperature following capture, however, pinealectomy in January—when all animals are sexually active—induces gonadal atrophy within 4 weeks. This clearly demonstrates that LP is stimulatory at this time of the subjective year.
Effects of a one‐hour light pulse on the timing of the circadian rhythm in melatonin secretion in rams
Authors: Kumar V. , Lincoln G. A.
Published: February 2007

Abstract: The effects of a 1‐hr light pulse on the timing of the circadian rhythm in the blood plasma concentration of melatonin were documented in Soay rams. Groups of 5 to 6 animals were transferred from short days (LD 8: 16) to constant dim red light (DD) for 6 days, and were exposed to a 1‐hr light pulse at one of 16 different times throughout 24 hr on day 3. Blood samples were collected hourly for 30 hr before (day 2–3) and after the light pulse (day 5–6), and the plasma concentrations of melatonin were measured by radioimmunoassay. The animals were allocated to experimental groups based on the circadian time (CT) when the light pulse was given using two hourly blocks through the circadian day; the onset of enhanced melatonin secretion (melatonin peak) was designated as CT 12. Under DD there was a clearly defined plasma melatonin rhythm in all animals. The mean duration of the melatonin peak was 13.24 ± 0.16 hr (n = 91) and the mean period between the onset of successive melatonin peaks was 23.55 ± 0.10 hr (n = 21). The effect of the 1‐hr light pulse on the time of onset of the melatonin peak varied significantly with the circadian time when the light pulse was given (ANOVA, P= 0.031). Light‐induced significant (pre‐ vs post‐pulse onset, Students t‐test, P < 0.05) phase delays in the onset of the melatonin peak in the early subjective day at CT 2.5 hrs (mean ø: ‐1.9 hr), and in the early subjective night at CT 12.5 and 14.5 (mean ø: ‐2.0 hrs), but not at other times. The light pulse never induced significant phase advances. The effects of the light pulse on the offset of plasma melatonin peak did not vary significantly with the time of the light pulse (ANOVA, P= 0.780), although significant differences in the pre‐ and post‐pulse offset occurred at CT 14.5 and 18.5 (mean ø: ‐1.5 hr). The differential changes in the onset and the offset of the melatonin peak resulted in changes in the duration of the peak (maximum difference between means: 3.8 hr). The results indicate that entrainment occurs under natural 24 hr LD cycles when light impinges on the early subjective night and induces a net phase delay, thus extending the period of the melatonin rhythm to 24 hr. This causes a close phase relationship between the end of the light period and the onset of the melatonin peak as occurs in sheep under natural cycles. The results are also consistent with a multiple oscillator governing melatonin secretion, and that differential entrainment of the component oscillators by light affects the duration of the melatonin peak.
Stability of melatonin in aqueous solution
Authors: Cavallo A. , Hassan M.
Published: February 2007

Abstract: Melatonin solutions are frequently used in human, animal, and in vitro research. Generally, fresh solutions are prepared, for fear of instability of mela‐tonin in solution. We tested the high‐performance liquid chromatography (HPLC) stability of melatonin in aqueous solutions stored room temperature, 4°C, and ‐70°C for up to 6 months. Solutions were prepared in a laminar flow hood using sterile technique, directly into sterile, pyrogen‐free glass vacuum vials for storage. Different concentrations were tested (1.0–113.0 μg/ml). There was no loss of po‐tency as assessed by HPLC, and the preparations remained sterile and pyrogen‐free. We conclude that melatonin solutions may be prepared in batches maintained in sterile, pyrogen‐free vials at 4°C or at ‐70°C until use within 6 months. This method will save on research time used for preparation of fresh solutions and will reduce the number of dose validation tests for each new experiment.
Immunomodulatory role of melatonin: specific binding sites in human and rodent lymphoid cells
Authors: Calvo Juan R. , Rafii‐EI‐ldrissi Mohammed , Pozo D. , Guerrero Juan M.
Published: February 2007

Abstract: This paper reviews the evidence that supports the hypothesis of the existence of specific binding sites for melatonin on immune cells. These binding sites have been described in human blood lymphocytes and granulocytes, and thymus, spleen, and bursa of Fabricius from different rodents and birds. The dissociation constant values of these binding sites are in the 0.1 ‐1 nM range, suggesting that melatonin may play a physiological role in lymphocyte regulation. Moreover, melatonin binding sites appear to be modulated by guanine nucleotides. Therefore, in addition to other mechanisms described for the regulation of immune function by melatonin, a direct mechanism of regulation can be involved via binding of melatonin by immunocompetent cells.
Melatonin and Cortisol assessment of circadian shifts in astronauts before flight
Authors: Whitson Peggy A. , Putcha Lakshmi , Chen Yu‐Ming , Baker Ellen
Published: February 2007

Abstract: Melatonin and Cortisol were measured in saliva and urine samples to assess the effectiveness of a 7‐day protocol combining bright‐light exposure with sleep shifting in eliciting a 12‐hr phase‐shift delay in eight U.S. Space Shuttle astronauts before launch. Baseline acrophases for 15 control subjects with normal sleep‐wake cycles were as follows: Cortisol (saliva) at 0700 (0730 in urine); melatonin (saliva) at 0130 (6‐hydroxymelatonin sulfate at 0230 in urine). Acrophases of the astronaut group fell within 2.5 hr of these values before the treatment protocols were begun. During the bright‐light and sleep‐shifting treatments, both absolute melatonin production and melatonin rhythmicity were diminished during the first 3 treatment days; total daily Cortisol levels remained constant throughout the treatment. By the fourth to sixth day of the 7‐day protocol, seven of the eight crew members showed phase delays in all four measures that fell within 2 hr of the expected 11‐ to 12‐hr shift. Although Cortisol and melatonin rhythms each corresponded with the phase shift, the rhythms in these two hormones did not correspond with each other during the transition.
Low and high melatonin excretors among healthy individuals
Authors: Bergiannaki Joanna‐Despina , Soldatos Constantin R. , Paparrigopoulos Thomas J. , Syrengelas Mariam , Stefanis Costas N.
Published: February 2007

Abstract: To meet the need of establishing firm normative data regarding the secretion/excretion of human melatonin, nighttime urinary melatonin of 16 healthy volunteers was measured in samples collected monthly over a period of 1 year. Low melatonin excretors (N = 8) were distinguished from high melatonin excretors (N = 8), based on a cut‐off mean melatonin value of 0.25 nmol/l. There was no overlap in any of the monthly melatonin values between the two groups, while their annual rhythms of melatonin excretion were not different in shape. Since no obvious factors (age, sex, height, weight, etc.) were responsible for the observed differences, the distinction between low and high nocturnal excretion and by inference secretion of melatonin most likely reflects genetically determined variable levels of the noradrenergic secretory drive and/or variable N‐acetyltransferase/hy‐droxyindole‐O‐methyltransferase enzymatic activity during the night.
Plasma melatonin in the horse: Measurements in natural photoperiod and in acutely extended darkness throughout the year
Authors: Guerin Michael V. , Deed Jim R. , Kennaway David J. , Matthews Colin D.
Published: February 2007

Abstract: Plasma melatonin was measured at the winter and summer solstices and the autumn and spring equinoxes in four mares held under natural conditions at 35°S. At all seasons the onset of the nightly elevated melatonin was coincident with or after the time of sunset and the melatonin offset after the time of sunrise. The duration of elevated melatonin was not different from the duration of natural scotophase for each season, with the duration of elevated melatonin longer in winter than the other seasons. Immediately following each 24 hr sampling two mares were resampled in acutely extended darkness to determine the melatonin profile of the endogenous rhythm of the circadian pacemaker, originating from the suprachiasmatic nuclei (SCN). At each season melatonin secretion commenced earlier and decreased later than that measured under the natural photoperiodic condition, suggesting that the expression of the melatonin rhythm is normally gated by natural environmental light both at dusk and dawn. The interval from the onset of melatonin measured under acutely extended darkness to the time of sunset was greater in the spring/ summer than the autumn/winter suggesting a possible alternating signal throughout the year. Thus the mare appears to exhibit a similar interaction between endogenous circadian rhythmic activity and the natural photoperiod as the ewe which may underlie the mechanism for timing reproductive activity through the year.
Melatonin reduces the severity of dextran‐induced colitis in mice
Authors: Pentney Patty T. , Bubenik George A.
Published: February 2007

Abstract: Melatonin administration reduces the severity of dextran sodium sulphate (DSS)‐induced colitis in mice. After 7 weeks of daily intraperitoneal melatonin administration (150 μg/kg), rectal bleeding and occult blood was eliminated in all mice in which colitis was induced by DSS. In addition the frequency and severity of focal lesions in the mucosa was dramatically reduced. Furthermore, weight loss and higher food consumption observed in DSS‐treated mice was reversed in DSS‐treated mice injected with melatonin. All treated groups exhibited significant alterations in goblet cell distribution as a result of DSS or melatonin administration. Surprisingly, serum melatonin levels were more than 10 times higher in mice that received DSS as compared to controls. The significant improvement in the conditions of melatonin‐treated mice might be due to its effect on the smooth muscles of the colon, the blood supply in the mucosa, its capability as an antioxidant and scavenger of free radicals, or its effect on the immune system of the gut. The higher plasma levels of melatonin in DSS‐treated mice might be due to a stress‐induced increase in the production of gastrointestinal (GIT) melatonin.
Minireview: Cell protective role of melatonin in the brain
Authors: Acufla‐Castroviejo Darfo , Escames Germaine , Macks Manuel , Hoyos Antono Muñóz , Carballo Antonio Molina , Arauzo Mariano , Montes Rosa , Vives Francisco
Published: February 2007

Abstract: In recent years an increasing amount of data has been published involving melatonin in the control of brain function. The pineal gland exerts a depressive influence on CNS excitability. This activity is linked to melatonin, since pharmacological doses of the hormone prevent seizures in several animal models. In addition, melatonin also has analgesic properties in these species. However, the sites and mechanism of melatonin action are not known. A role for the pineal gland and its hormone melatonin as a homeostatic system controlling brain excitability has been proposed, and GABA‐containing neurons may be involved in some central action of melatonin. There is evidence supporting a role of melatonin in the regulation of the GABA‐benzodiazepine receptor complex, and it appears that melatonin potentiates this inhibitory neurotransmitter system in brain. Melatonin does not bind to GABA or benzodiazepine binding sites themselves, because in vitro binding data showed that melatonin is a weak competitor of benzodiazepine binding in brain membranes at concentrations greater than 10−5 M. The effect of melatonin on brain activity also involves the participation of corticotropic and opioid peptides, and the existence of an opioid‐antiopioid homeostatic system is proposed, with the GABA‐benzodiazepine receptor complex as an effector. Moreover, the interaction of melatonin with corticotropic peptides and mitochondrial benzodiazepine receptors may result in a participation of neurosteroids in the control of GABA activity and function. The most recently available data from biochemical and electrophysiological studies support the possibility that the anticonvulsant and depressive effects of melatonin on neuron activity may depend on its antioxidant and antiexcitotoxic roles, acting as a free radical scavenger and regulating brain glutamate receptors. The full characterization of the nuclear melatonin receptor explains the genomic effects of melatonin, opening a new perspective regarding actions and roles of melatonin as a cellular protector.
The midline pineal “eye”: MR and CT characteristics of the pineal gland with and without benign cyst formation
Authors: Jinkins J.R. , Xiong L , Reiter R.J.
Published: February 2007

Abstract: The purpose of this study was to evaluate the magnetic resonance imaging characteristics of pineal cysts and pineal calcifications and to determine the incidence of benign pineal cysts. Two‐hundred‐fifty magnetic resonance examinations were retrospectively examined for the incidence of pineal cysts. In addition, 60 collected cases of pineal cysts were evaluated with regard to cross sectional diameter and magnetic resonance signal characteristics. Finally, the magnetic resonance signal characteristics of pineal tissue in 50 patients were compared to companion computed tomographic scans that were scrutinized for the presence or absence of calcification. The incidence of pineal cysts as revealed by magnetic resonance imaging in this study was 10.8%. The minimal and maximal measurements ranged from a low of 2×2×2 mm to a high of 10×12×10 mm. The magnetic resonance signal intensities of pineal cyst as compared to cerebrospinal fluid were iso‐ or hyperintense on all magnetic resonance sequences in the majority of cases. Calcifications of the pineal gland as revealed by computed tomography tended to be isointense to gray matter if the calcifications were small and hypointense to gray matter if large on all magnetic resonance acquisitions. A careful analysis of the magnetic resonance signal characteristics enables the recognition of moderate‐ to large‐sized pineal calcifications and their differentiation from large pineal cysts. However, small cysts of the pineal gland can be difficult or impossible to distinguish on magnetic resonance imaging from calcifications without comparison with computed tomography.
Expression of the melatonin receptor in Xenopus laevis: A comparative study between protein and mRNA distribution
Authors: Mazzucchelli Cristina , Capsoni Simona , Angeloni Deborah , Fraschini Franco , Stankov Bojidar
Published: February 2007

Abstract: Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis performed on total RNA from different tissues of Xenopus laevis showed that the melatonin receptor gene cloned from dermal melanophores is expressed in the whole brain, skin, and retina, and that apart from the ovary, there is no expression in tissues having origin outside the central nervous system. Comparative studies using in vitro autoradiography and in situ hybridization demonstrated that the melatonin receptor is expressed with discrete allocation in Xenopus brain. Though the distribution pattern of the specific messenger RNA conforms well with that of the corresponding receptor protein, it is not always coincident.
The effect of melatonin on cleavage rate of C57BL/6 and CB A/Ca preimplantation embryos cultured in vitro
Authors: McElhinny Abigail S. , Davis Fred C. , Warner Carol M.
Published: February 2007

Abstract: There is growing interest in using melatonin as a therapeutic agent for the treatment of a variety of medical conditions, including cancer, heart disease, glaucoma, stress, jet lag, and sleep disorders. In addition, melatonin is being evaluated in a clinical trial to test its efficacy as an oral contraceptive. In order to test any possible adverse effects of melatonin on preimplantation embryos, we used the mouse as a model system. Two strains of mice, a Ped fast, melatonin‐deficient strain, C57BL/6, and a Ped slow strain previously found to have detectable melatonin levels at nighttime, CBA/Ca, were studied. Two cell embryos were incubated with melatonin concentrations from 10−5 M to 10−13 M for 48 or 72 hours and the number of cells per embryo assessed quantitatively at the end of the incubation period. We used sufficiently high levels of melatonin to mimic the pharmacological concentration used in the oral contraceptive. It was found that there was no effect of melatonin on embryos from either mouse strain at any of the concentrations tested. Our results suggest that if conception occurs while melatonin is being administered to treat a range of conditions, it would not adversely affect the embryo.
CGP 52608‐induced cyst formation in dinoflagellates: Possible involvement of a nuclear receptor for melatonin
Authors: Tsitn Siu‐Tai , Wong Joseph T.Y. , Wong Yung H.
Published: February 2007

Abstract: Melatonin has been shown to regulate gene transcription through RZR/ROR nuclear receptors in mammalian cells. Thiazolidine dione CGP 52608 is a selective agonist of RZR/ROR receptors with little or no affinity for the cell surface G protein‐coupled melatonin receptors. In this study, we addressed whether nuclear signaling may be involved in indoleamine‐induced encystment of the unicellular dinoflagellates by examining their responses to CGP 52608. Three species of dinoflagellates (Alexandrium catenella, Amphidinium carterae, and Crypthecodinium cohnii) encysted in the presence of CGP 52608 and the responses were reversible and dose‐dependent. Since a previous study has implicated the involvement of G proteins in mediating indoleamine‐induced encystment of dinoflagellates, we explored the possibility of cross‐talks between G protein‐dependent and nuclear signaling pathways. The responses of A. catenella to either mastoparan (a direct activator of mammalian G proteins) or indoleamines were assessed in the presence or absence of CGP 52608. Interestingly, CGP 52608 synergized with either indoleamines or mastoparan to produce a more rapid encystment response. These findings suggest that nuclear signaling may be involved in the indoleamine‐induced encystment of dinoflagellates.
Melatonin in relation to physiology in adult humans
Authors: Cagnacci Angelo
Published: February 2007

Abstract: The role exerted by melatonin in human physiology has not been completely ascertained. Melatonin levels have been measured in different physiopathological conditions, but the effects induced by melatonin administration or withdrawal have been tested only recently. Some effects have been clearly documented. Melatonin has hypothermic properties, and its nocturnal secretion generates about 40% of the amplitude of the circadian body temperature rhythm. Melatonin has sleep inducing properties, and exerts important activities in the regulation of circadian rhythms. Melatonin is capable of phase shifting human circadian rhythms, of entraining free‐running circadian rhythms, and of antagonizing phase shifts induced by nighttime exposure to light. Its effect on human reproduction is not completely clear, but stimulatory effects on gonadotropin secretion have been reported in the follicular phase of the menstrual cycle. Direct actions on ovarian cells and spermatozoa have been also documented. Beside these, new important actions for melatonin may be proved. Melatonin may exert protective effects on the cardiovascular system, by reducing the risk of atherosclerosis and hypertension, and may influence immune responses. Finally, by acting as an antioxidant, melatonin could be important in slowing the processes of ageing.
Afternoon injections of melatonin in the Djungarian hamster Phodopus sungorus: Long lasting sex‐specific effects and influence of acute treatment on the endogenous pineal melatonin rhythm
Authors: Niklowitz Petra , Bockers Tobias M. , Lerchl Alexander
Published: February 2007

Abstract: The effects of exogenous melatonin on gonadal function and on the endogenous melatonin profiles of male and female Djungarian hamsters were investigated. Daily afternoon subcutaneous injections of melatonin (50 μ.g) in hamsters kept in long photoperiods (LD 16: 8) led to gonadal inhibition in all the treated females (n=13) but in only 2 of 13 males within the treatment period of 8 weeks (uteri: 244±11 mg in controls vs. 79±4 mg in treated hamsters, P<0.001; ovaries: 13.6±0.6 mg in controls vs. 7.9±0.7 mg in treated hamsters, P<0.001; testes: 1,021±54 mg in controls vs. 732±100 mg in treated hamsters, P<0.05; and accessory glands: 641±38 mg in controls vs. 548±70 mg in treated hamsters, P>0.05). These results indicate that there are some circumstances under which the gonadal responses of the reproductive organs of male and female Djungarian hamsters differ. Interestingly, pineal concentrations of melatonin were found to be significantly higher in males (P<0.01), possibly indicating a more robust endogenous supply with the hormone, whereas serum melatonin levels were not significantly different between males and females. However, the subcutaneous injection of melatonin (5, 25, and 125 μg) exerted no acute effect on the endogenous, circadian melatonin‐profile, independent of dosage and sex.
Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma
Authors: Lissoni R , Brivio O. , Brivio F. , Barni S. , Tancini G. , Crippa D. , Meregalli S.
Published: February 2007

Abstract: Several experimental studies have shown that melatonin has an oncostatic action, either by stimulating host antitumor immune defenses or by directly inhibiting the growth of some cancer histotypes, including melanoma. Our previous clinical studies demonstrated that melatonin may induce stabilization of the disease in untreatable metastatic solid tumor patients, and these results have been confirmed by others, at least in patients with metastatic melanoma. On the contrary, at present there are no data related to the possible efficacy of melatonin as an adjuvant endocrine therapy. This study was performed to investigate the impact of melatonin therapy on the disease‐free survival (DFS) in melanoma patients surgically treated for regional node recurrence. The study included 30 node‐relapsed melanoma patients, who were randomized to receive no treatment or adjuvant therapy of melatonin (20 mg/day orally in the evening) every day until disease progression. After a median follow‐up of 31 months, the percent of DFS was significantly higher in melatonin‐treated individuals than in controls. The DFS curve was also significantly longer in melatonin group than in controls. No melatonin‐related toxicity was observed. This preliminary study suggests that an adjuvant endocrine therapy with melatonin may be effective in preventing disease progression in node‐relapsed melanoma patients.
A combined immunohistochemical and electron microscopic study of the second cell type in the developing sheep pineal gland
Authors: Franco Antonio , Regodon Sergio , Masot Antonio J. , Redondo Eloy
Published: February 2007

ABSTRACT: Ultrastructural and immunohistochemical techniques were used to study the second cell type in sheep embryo pineal glands. Thirty‐two embryos were studied from day 54 of development through birth. Specimens were arranged in four age groups, defined in terms of the most relevant histological features: Group 1 (54‐67 days of prenatal development), Group 2 (71‐92 days), Group 3 (98‐113 days), and Group 4 (118–150 days). At 98 days, a second cell type was observed which differed from pinealoblasts and showed uniform ultrastructural characteristics similar to those of astrocytes in the central nervous system. Ultrastructural homogeneity was not matched by the results of histochemical and immunohistochemical analysis: while all Type II cells stained positive to phosphotungstic acid hematoxylin, only 50% expressed glial fibrillary acidic protein. In the course of ovine intrauterine development, the vascular affinity of this second cell population, composed of glial‐like or astrocytic cells at varying stages of maturity, leads to the formation of a limiting pineal barrier. This barrier may constitute the morphological expression of a hypothetical functional involvement in the exchange of substances between blood and pineal parenchyma.
Autoradiographic localization of 2[125I]iodomelatonin binding sites in the gastrointestinal tract of mammals including humans and birds
Authors: Poon A.M.S. , Chow RH. , Mak A.S.Y. , Pang S.F.
Published: February 2007

ABSTRACT: In‐vitro autoradiography was utilized to compare the distribution of 2[125I]iodomelatonin binding sites or putative melatonin receptors in the gastrointestinal tracts of humans, guinea pigs, mice, rats, hamsters, rabbits, ducks, chickens, pigeons, and quail. In humans, binding was detected in the mucosa of the colon, caecum, appendix, and on their blood vessels but not in the ileum. In the other mammals, significant binding was only demonstrated in the mucosa of the rabbit rectum, mouse colon, mouse rectum, and guinea pig ileum. The distribution of 2[125I]iodomelatonin binding in the avian gut varied with species. In the esophagus, binding was present in the lamina propria and blood vessels of all four birds. However, only the lamina propria of the chicken and quail proventriculus and ventriculus showed positive binding. For the duodenum and ileum, binding was very strong in the duck lamina propria, weak in the chicken lamina propria, and absent in the quail. In contrast, the pigeon muscle layer was weakly positive. The most striking species difference was found in the caecum where the duck lamina propria showed very strong binding, while the chicken lamina propria was only weakly positive. Conversely, the caecal muscle layer was strongly positive in chicken and quail but negative in duck and pigeon. In the rectum, a similar but less intense pattern of distribution was observed. The tremendous diversity in the distribution of 2[125I]iodomelatonin binding sites in the gastrointestinal tract is in accord with the hypothesis that melatonin may serve different functions in the gut of different species.
A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first‐line treatment of advanced non‐small cell lung cancer patients in a poor clinical state
Authors: Lissoni P. , Paolorossi F. , Ardizzoia A. , Barni S. , Chilelli M. , Mancuso M. , Tancini G. , Conti A. , Maestroni G.J.M.
Published: February 2007

ABSTRACT: Recent studies suggest that the pineal hormone melatonin may reduce chemotherapy‐induced immune and bone marrow damage. In addition, melatonin may exert potential oncostatic effects either by stimulating host anticancer immune defenses or by inhibiting tumor growth factor production. On this basis, we have performed a randomized study of chemotherapy alone vs. chemotherapy plus melatonin in advanced non‐small cell lung cancer patients (NSCLC) with poor clinical status. The study included 70 consecutive advanced NSCLC patients who were randomized to receive chemotherapy alone with cisplatin (20 mg/m2/day i.v. for 3 days) and etoposide (100 mg/m2/day i.v. for 3 days) or chemotherapy plus melatonin (20 mg/day orally in the evening). Cycles were repeated at 21‐day intervals. Clinical response and toxicity were evaluated according to World Health Organization criteria. A complete response (CR) was achieved in 1/34 patients concomitantly treated with melatonin and in none of the patients receiving chemotherapy alone. Partial response (PR) occurred in 10/34 and in 6/36 patients treated with or without melatonin, respectively. Thus, the tumor response rate was higher in patients receiving melatonin (11/34 vs. 6/35), without, however, statistically significant differences. The percent of 1‐year survival was significantly higher in patients treated with melatonin plus chemotherapy than in those who received chemotherapy alone (15/34 vs. 7/36, P < 0.05). Finally, chemotherapy was well tolerated in patients receiving melatonin, and in particular the frequency of myelosuppression, neuropathy, and cachexia was significantly lower in the melatonin group. This study shows that the concomitant administration of melatonin may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition.
Inhibition of hepatic tryptophan‐2,3‐dioxygenase: Superior potency of melatonin over serotonin
Authors: Walsh Harold A. , Daya Saniy
Published: February 2007

ABSTRACT: In view of the biogenic amine deficiency hypothesis of depression and the contentious claim that hepatic tryptophan‐2,3‐dioxygenase (TDO) is the major peripheral determinant of brain tryptophan, brain serotonin (5‐HT), and ultimately melatonin, the regulation of TDO by melatonin and 5‐HT is investigated and discussed. It is concluded that TDO activity is regulated differentially by melatonin and 5‐HT. Melatonin is a competitive inhibitor of TDO and 5‐HT is predominantly an allosteric inhibitor. In the presence of 5‐HT the effects of melatonin are nullified. However melatonin alone is a more potent inhibitor of TDO. Melatonin is also shown to be a reversible negative effector of TDO.
Influence of melatonin and serotonin on glucose‐stimulated insulin release from perifused rat pancreatic islets in vitro
Authors: Peschke Elmar , Peschke Dorothee , Hammer Thomas , Csernus Valer
Published: February 2007

Peschke E, Peschke D, Hammer T, Csernus V. Influence of melatonin and serotonin on glucose‐stimulated insulin release from perifused rat pancreatic islets in vitro. J. Pineal Res. 1997; 23:156–163. © Munksgaard, Copenhagen

Insulin plays a key role in the control of glucose homeostasis in mammals. Insulin secretion is regulated by a coordinated interplay of several factors. The role of the indoleamines in the control of insulin secretion has not been fully elucidated yet. The present study was addressed to investigate the function of melatonin and serotonin in the direct control of insulin secretion from the pancreatic islets. Explanted rat Langerhans' islets were treated with melatonin or serotonin while also being exposed to specific (glucose) or non‐specific (KC1) stimulus either in a pulsatile or long‐term manner in a perifusion system. Insulin content from the effluent tissue culture media was analyzed with RIA. Pulsatile administration of melatonin and serotonin alone did not alter the basal insulin secretion from the explanted islets even at pharmacological (5 μM) level. However, insulin response to specific (glucose) or non‐specific (KC1) stimulus was significantly reduced while the islets were treated with melatonin (3 to 12 hr, 10 nM to 5 μM). This effect was reversible and repeatable. Both the start and end of the effect was rapid, evolving and disappearing within 10 min. On the other hand, under similar experimental protocol, serotonin (at 5 μM concentration) significantly enhanced both glucose and KC1 stimulated insulin release. Since the effect of the nonspecific stimulation (with KC1) was also altered, melatonin and serotonin seem to alter not only the release but also the synthesis of the insulin. Our data show that melatonin and serotonin have a direct effect on the insulin secretion from the pancreatic islets.
An essential role for ovarian inhibin in pineal gland‐mediated anestrus in Syrian hamsters
Authors: Benson Bryant , McAsey Mary E.
Published: February 2007

ABSTRACT: When transferred from long photoperiod (LP) to short photoperiod (SP), female Syrian hamsters exhibit depressions of follicle stimulating hormone (FSH) and follicular development, cessation of ovulation, and marked ovarian interstitial tissue hyperplasia. Pinealectomy prevents these effects of SP. The object of this study was to determine the role of inhibin in the regulation of FSH during SP‐induced anestrus. Adult LSH/SsLak hamsters maintained in LP (LD 14: 10 hr) were transferred to SP (LD 8: 16 hr) on the day of estrus, and groups of animals killed at either 16.00 hr on proestrus or 08.00 hr on estrus during each of five consecutive 4‐day estrus cycles after transfer. Groups of females that became anestrus in SP were killed either at 08.00 or 16.00 hr, 12 days after the last observed estrus discharge. Compared to LP controls, serum FSH levels on estrus increased significantly (P<0.01) during the first two cycles in SP before declining to concentrations that were significantly lower than control values (P<0.01). Serum inhibin levels increased significantly by the third, fourth, and five days of estrus in SP. Regression analysis revealed a significant inverse correlation between serum inhibin and FSH levels on estrus during SP exposure (F=0.021) but not on proestrus. Relative levels of inhibin a‐ andβA‐subunit mRNAs were lower in ovaries from SP proestrus and anestrus females killed at 16.00 hr as compared to those from proestrus LP controls; they were elevated in ovaries from SP estrus and anestrus females killed at 08.00 hr compared to those from estrus LP controls. The absence of antral follicles on estrus in the last cycles of SP and anestrus suggests that the increase in circulating inhibin and inhibin mRNAs may be derived from hyperplastic interstitium. These observations suggest that inhibin may play an essential role in suppressing FSH secretion during pineal gland‐mediated anestrus in Syrian hamsters.
Physiological concentrations of melatonin inhibit the norepinephrine‐induced activation of prostaglandin E2 and cyclic AMP production in rat hypothalamus: A mechanism involving inhibition of nitric oxide synthase
Authors: Bettahi Ilham , Guerrero Juan M. , Reiter Russel J. , Osuna Carmen
Published: February 2007

ABSTRACT: In this paper, we summarize the results of in vitro studies showing that physiological concentrations of melatonin inhibit the norepinephrine‐induced activation of prostaglandin E2 (PGE2) and cyclic AMP production in rat medial basal hypothalamus (MBH). Interestingly, a concentration of melatonin as low as 1 nM, which is roughly equivalent to the nocturnal serum physiological concentration of the hormone in the rat, significantly inhibit PGE2 and cyclic AMP production in the MBH. The suppressive effect of melatonin may be mediated by an inhibition of nitric oxide synthase (NOS) activity, since the stimulatory effect of sodium nitroprusside (SNP), a spontaneous generator of NO, was not prevented by melatonin. Melatonin also inhibited NOS activity in rat MBH in a dose‐dependent manner. The results suggest the existence of a new or an ancillary means by which melatonin may regulate the physiology of the hypothalamus‐pituitary unit.
Effect of estrogen on melatonin synthesis in female peripubertal rats as related to adenylate cyclase activity
Authors: Okatani Yuji , Hayashi Kazutoshi , Sagara Yusuke
Published: February 2007

Okatani Y, Hayashi K, Sagara Y. Effect of estrogen on melatonin synthesis in female peripubertal rats as related: Relation to adenylate cyclase activity. J. Pineal Res. 1998; 25:245–250. © Munksgaard, Copenhagen

To determine the mechanism for the modulatory effect of estrogen on melatonin synthesis, we evaluated the effects of estrogen on the activity of adenylate cyclase in female Sprague‐Dawley rats of peripubertal age. Adenylate cyclase activity was measured in homogenates of pineal glands from rats aged 3 and 10 weeks in the mid‐dark and in the mid‐light. Ovariectomy was performed and a subcutaneous injection of estradiol benzoate (E2B) was administered daily starting at the age of 6 weeks. A peak in adenylate cyclase activity in the pineal gland was observed in untreated (control) rats with intact ovaries at 4 weeks. Ovariectomy at week 6 led to significant increases in the activity of adenylate cyclase at week 8. At week 10, adenylate cyclase activity resembled that of control animals. The subcutaneous injection of E2B (1.0 (Ag/day) suppressed the increase in adenylate cyclase activity induced by ovariectomy, similar to the level seen in control rats with intact ovaries. The changes in the mid‐light activity of pineal adenylate cyclase resembled that seen at the mid‐dark with the value being significantly lower than that observed in the mid‐dark. Such changes in the mid‐dark activity of adenylate cyclase resembled those observed with N‐acetyltransferase (NAT) at the same time, as previously described. Results suggest that estrogen modulates adenylate cyclase activity in the pineal gland of peripubertal female rats. The decline in melatonin synthesis during puberty may be related to an increase in estrogen level. The inhibitory effect of estrogen on melatonin synthesis appeared to be mediated by a change in the norepinephrine‐induced stimulation of pineal adenylate cyclase activity.
Oxidative stress in diabetic rats induced by streptozotocin: Protective effects of melatonin
Authors: Montilla Pedro López , Vargas José Fresno , Túnez Isaac Fiñana , Carmen M. , de Agueda Muñoz , Valdelvira M. Elías Díaz , Cabrera Emilio Sãnchez
Published: February 2007

Abstract: We have studied the effect of the administration of two doses of melatonin (melatonin 100 and melatonin 200 μg/kg bw) on diabetes and oxidative stress experimentally induced by the injection of streptozotocin (STZ) in female Wistar rats. STZ was injected as a single dose (60 mg/kg i.p. in buffered citrate solution, pH 4.0) and melatonin (melatonin 100, 100 μg/kg/day i.p.; melatonin 200, 200 μg/kg/day i.p.) beginning 3 days before diabetes induction and continuing until the end of the study (8 weeks). The parameters analysed to evaluate oxidative stress and the diabetic state were a) for oxidative stress, changes of lipoperoxides (i.e., malondialdehyde, MDA) in plasma and erythrocytes and the changes in reduced glutathione (GSH) in erythrocytes and b) for diabetes, changes in glycemia, lipids (triglycerides: TG; total cholesterol: TC; HDL‐cholesterol, HDL‐c), percentage of glycosylated hemoglobin (Hb%), and plasma fructosamine. The injection of STZ caused significant increases in the levels of glycemia, percentage of glycosylated hemoglobin, fructosamine, cholesterol, triglycerides, and lipoperoxides in plasma and erythrocytes, whereas it decreased the levels of HDL‐c and the GSH content in erythrocytes. The melatonin 100 dose reduced significantly all these increases, except the percentage of glycosylated hemoglobin. With regard to the decreases of plasma HDL‐c and GSH content in erythrocytes, this melatonin dose returned them to normal levels. The melatonin 200 dose produced similar changes, though the effects were especially noticeable in the decrease of glycemia (55% vs. diabetes), percentage of hemoglobin (P < 0.001 vs diabetes), and fructosamine (31% vs. diabetes). This dose also reversed the decreases of HDL‐c and GSH in erythrocytes. Both doses of melatonin caused significant reduction of the percentage of glycosylated hemoglobin in those groups that were non‐diabetic. These illustrate the protective effect of melatonin against oxidative stress and the severity of diabetes induced by STZ. In particular, this study confirms two facts: 1) the powerful antioxidant action of this pineal indole and 2) the importance of the severity of oxidative stress to maintain hyperglycemia and protein glycosylation, two pathogenetic cornerstones indicative of diabetic complications. Melatonin reduces remarkably the degree of lipoperoxidation, hyperglycemia, and protein glycosylation, which gives hope to a promising perspective of this product, together with other biological antioxidants, in the treatment of diabetic complications where oxidative stress, either in a high or in a low degree, is present.
Short photoperiod affects reproductive function but not dehydroepiandrosterone concentrations in male deer mice (Peromyscus maniculatus)
Authors: Kriegsfeld Lance J. , Nelson Randy J.
Published: February 2007

Abstract: Cessation of breeding is central among the suite of winter‐coping strategies used by small rodents to survive energy‐demanding winter conditions. Animals use photoperiod to predict the onset of winter and initiate, well in advance of deteriorating conditions, seasonal adaptations. Exposure to short photoperiod leads to regression of the reproductive system in long‐day breeding animals. Likewise, exposure to short days leads to enhanced immune function among several rodent species studied. Because dehydroepiandrosterone (DHEA) increases immune function in virtually all studies reported to date, we sought to determine if DHEA concentrations might be influenced by photoperiod, thereby suggesting a mechanism whereby short photoperiod may enhance immune function. Male deer mice (Peromyscus maniculatus) were exposed to either short or long days for 10 weeks. Short photoperiods caused significant reduction in all reproductive organs measured relative to animals housed in long days. However, DHEA concentrations did not differ between short‐ and long‐day mice. Taken together, these data suggest that short‐day enhancement of immune function in deer mice is independent of DHEA concentrations.