Melatonin and The Inhibition of Fibroblasts
Effect of melatonin on normal and sclerodermic skin fibroblast proliferation. Carossino AM Lombardi A Matucci-Cerinic M Pignone A Cagnoni M, Clin Exp Rheumatol (1996 Sep-Oct) 14(5):493-8
OBJECTIVE: We studied the effect of melatonin (MLT) (N-acetyl 5- methoxytryptamine) on the growth rate of normal skin fibroblasts and of fibroblasts from involved and apparently uninvolved skin of patients affected by systemic sclerosis (SSc). METHODS: The growth rate was evaluated on the basis of growth curves and a 3H-thymidine incorporation assay. RESULTS: Our results demonstrate that a dose of 200 micrograms/ml of MLT inhibits (> 80%) both control and SSc fibroblasts. Inhibition was dose-dependent and was greater than 70% for MLT concentrations of 100 micrograms/ml, 200 micrograms/ml and 400 micrograms/ml. 3H-thymidine incorporation was correlated with the effect on the growth curves (81% at 200 micrograms/ml of MLT). In contrast, at a low dosage of 6 micrograms/ml, MLT exerted a stimulatory effect on cell proliferation in all the cell lines analyzed. Cell viability was not affected by MLT at any of the concentrations tested. A recovery study indicated that replacement of MLT-containing medium with MLT-free medium resulted in a re-establishment of cell growth. CONCLUSIONS: These results suggest that MLT, at higher dosages, is a potent inhibitor of the proliferation of fibroblasts derived from the skin of healthy and SSc patients.
Transdermal Delivery of Melatonin
Lee BJ Parrott KA Ayres JW Sack RL, Res Commun Mol Pathol Pharmacol (1994 Sep) 85(3):337-46
A transdermal delivery device (TDD)1 was applied to four human subjects to investigate whether melatonin (MT) could penetrate through human skin. The TDD (total surface area of 3.80 cm2) was applied to the forearm of each subject. Plasma MT concentrations increased above baseline in approximately 2-4 hours, although steady state was not achieved in the 8-hour study period. Intersubject variation of plasma MT among four subjects was noted. Urinary excretion of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT in humans, increased as plasma MT concentrations increased. Cumulative amounts of urinary 6-STMT increased over a 6-hour period when the TDD was applied and were three times greater than in controls. The urinary excretion rate of 6-STMT was statistically correlated with plasma MT concentration among subjects (r2 = 0.77). These data suggest that the urinary excretion rate of 6-STMT can be used as an index of MT plasma concentrations in human subjects. An intersubject variability in both plasma MT concentration and urinary excretion rate of 6-STMT was noted; still, MT can be delivered transdermally in human subjects.
Melatonin secretion related to side-effects of beta-blockers from the central nervous system
Brismar K; Hylander B; Eliasson K; Rossner S; Wetterberg L Department of Endocrinology, Karolinska Hospital, Sweden Acta Med Scand (SWEDEN) 1988, 223 (6) p525-30,
In two studies of hypertensive patients the relationship between beta-blocker-induced CNS side-effects and the nightly urinary secretion of melatonin was analysed. In one group (n = 10) placebo, atenolol (mean dose 86 mg/day) or propranolol (mean dose 305 mg/day) were given in a double-blind, randomised design. In the other (n = 13) 100-400 mg metoprolol was given daily (mean dose 197 mg). After 4 weeks of treatment all beta-blockers reduced melatonin excretion, but the effect was significant only for metoprolol. Sleep disturbance records revealed more disturbed nights in the metoprolol group compared with the propranolol and the atenolol groups, even when the difference in age between the groups was controlled for. In the metoprolol group a significant relationship (p less than 0.05) was found between the fall in melatonin and the percentage of disturbed nights. Severe CNS side-effects, such as nightmares, occurred only in patients treated with metoprolol (21%), which in all cases were accompanied by low levels of melatonin. Our data suggest that the CNS side-effects during beta-blockade are related to a reduction of melatonin levels.
Oxidative damage caused by free radicals produced during catecholamine autoxidation: Protective effects of O-methylation and melatonin
Miller J.W.; Selhub J.; Joseph J.A.
Department of Pharmacology, Duke University Medical Center, Box 3813, Durham, NC 27710 USA
Free Radical Biology and Medicine (USA), 1996, 21/2 (241-249)
Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinson's disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum beta-phycoerythrin (beta-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O- methyldopa significantly decreased the rate of beta-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L- dopa, the rate of beta-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brain's antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.
Protective effect of melatonin against hippocampal DNA damage induced by intraperitonealadministration of kainate to rats
Uz T; Giusti P; Franceschini D; Kharlamov A; Manev H
Neurosciences Research Center, Allegheny-Singer Research Institute,
Pittsburgh, PA 15212, USANeuroscience (UNITED STATES) Aug 1996, 73 (3) p631-6
The pineal hormone melatonin protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors and from oxidative stress-induced DNA damage and apoptosis. Intraperitoneal injection on kainate into experimental animals triggers DNA damage in several brain areas, including the hippocampus. It is not clear whether melatonin is neuroprotective in vivo. In this study, we tested the in vivo efficacy of melatonin in preventing kainate-induced DNA damage in the hippocampus of adult male Wistar rats. Melatonin and kainate were injected i.p. Rats were killed six to 72 h later and their hippocampi were examined for evidence of DNA damage (in situ dUTP-end-labeling, i.e. TUNEL staining) and for cell viability (Nissl staining). Quantitative assay was performed using computerized image analysis. At 48 and 72 h after kainate we found TUNEL-positive cells in the CA1 region of the hippocampus; in the adjacent sections that were Nissl-stained, we found evidence of cell loss. Both the number of TUNEL-positive cells and the loss of Nissl staining were reduced by i.p. administration of melatonin (4 x 2.5 mg/kg; i.e. 20 min before kainate, immediately after, and 1 and 2 h after the kainate). Our results suggest that melatonin might reduce the extent of cell damage associated with pathologies such as epilepsy that involve the activation of kainate-sensitive glutamate receptors.
Neuroprotection by melatonin from kainate-induced excitotoxicity in rats
Giusti P; Lipartiti M; Franceschini D; Schiavo N; Floreani
M; Manev HDepartment of Pharmacology, University of Padua, Italy
FASEB J (UNITED STATES) Jun 1996, 10 (8) p891-6
In this study, we injected 10 mg/kg kainate i.p. into rats. This resulted in a brain injury, which we quantified in the hippocampus, the amygdala, and the pyriform cortex. Neuronal damage was preceded by a set of typical behavioral signs and by biochemical changes (noradrenaline decrease and 5-hydroxyindoleacetic acid increase) in the affected brain areas. Melatonin (2.5 mg/kg) was injected i.p. four times: 20 min before kainate, immediately after, and 1 and 2 h after the kainate. The cumulative dose of 10 mg/kg melatonin prevented kainate-induced neuronal death as well as behavioral and biochemical disturbances. A possible mechanism of melatonin-provided neuroprotection lies in its antioxidant action. Our results suggest that melatonin holds potential for the treatment of pathologies such as epilepsy-associated brain damage, stroke, and brain trauma.
The hypothermic effect of melatonin on core body temperature: Is more better?
Dawson D; Gibbon S; Singh P
Centre for Sleep Research, School of Psychology, University of South Australia, Queen Elizabeth Hospital, Australia
J Pineal Res (DENMARK) May 1996, 20 (4) p192-7
Recent studies have shown that melatonin is both hypnotic and hypothermic at physiological levels. Indeed, the hypnotic effect may be mediated via the hypothermic action. If this is the case, it is important to explore the dose-response relationships for the thermoregulatory effects of melatonin. Four groups of eight healthy adults (n = 32), aged between 18 and 38, each underwent two 12-hr bedrest protocols in which core body temperature (CT) and plasma melatonin levels were measured concurrently between 0800 and 2000 hr. For each group, subjects ingested either sucrose placebo or a 0.1, 0.5, 1.0, or 5.0 mg melatonin capsule at 1600 hr in a double-blind counterbalanced cross-over design. Melatonin was absorbed rapidly, with peak levels being reached after 1 hr at all dose levels. Mean peak plasma melatonin levels increased from physiological to pharmacological levels in a dose-dependent manner. Elimination for all dose levels was rapid, with mean plasma half-lives between 33 and 47 min. At the lower doses the mean drop in CT was between 0.05 and 0.15 degrees C and took between 2 and 3 hr. At the higher doses (1.0 and 5.0 mg), CT fell by 0.25-0.3 degrees C within 30-60 min following ingestion and at the highest dose (5 mg) remained suppressed for the duration of the study. While the magnitude and duration of the drop increased in what appeared to be a dose-dependent manner, it is unlikely that this relationship reflects a simple dose-response curve. There was considerable variability in plasma profiles following administration, particularly at the two lowest doses (0.1 and 0.5 mg). The lower mean drop in CT probably reflects the lower proportion of subjects achieving physiological plasma levels, and therefore a hypothermic effect, at the two lowest doses. If melatonin is to be used to improve sleep onset and maintenance by lowering CT, doses between 1.0 and 5.0 mg appear to be the lowest that produce a consistent drop in CT across all subjects.
The zinc pool is involved in the immune-reconstituting effect of melatonin in pinealectomized mice
Mocchegiani E; Bulian D; Santarelli L; Tibaldi A; Muzzioli M; Lesnikov V; Pierpaoli W; Fabris
Gerontol. Res. Dept., Italian National Research Centres on Aging, Ancona, Italy
J Pharmacol Exp Ther (U.S.) Jun 1996, 277 (3) p1200-8
Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.
Melatonin and the endocrine role of the pineal organ
Argentina Curr Topics Exp. Endocrin. (USA), 1974, Vol. 2 (107-128)
Fourteen years have elapsed since the discovery of the pineal hormone melatonin; since then, interest in the physiology of the pineal has grown steadily, as has the knowledge of the contribution of the pineal to the economy of the body. Sufficient information is now available to encourage acceptance of the 'melatonin hypothesis of pineal function', put forth in 1965 by Wurtman and Exelrod. This hypothesis holds that the mammalian pineal synthesized and secretes melatonin at a rate inversely dependent on environmental lighting, and receives signals concerning the lighting milieu via a complex pathway involving the retinas the brain, and the sympathetic neurons to and from the superior cervical ganglia. Melatonin ultimately enters the general circulation, either by direct secretion from the pinealocytes or indirectly via the CSF. Melatonin acts on the brain, and perhaps directly, to depress the rate of gonadal maturation, and to interfere with subsequent gonadal function and cyclicity; it may also modify the functions of the thyroid and the adrenal cortex, sice melatonin ijnections haven been shown to inhibit thyroid hormone secretion rate and the secretion of adrenal steroids. It seems likely that the pineal participates, through the secretion of melatonin, in the control of certain neuroendocrine and neurophysiological rhythms; it may also mediate some of the effects of light on gonadal maturation, the ovulatory cycle, and the secretion of pituitary hormones. This is a good review article with some 200 references.
Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism
Israel Journal of Autism and Developmental Disorders (USA), 1995, 25/6 (641-654)
An abnormal circadian pattern of melatonin was found in a group of young adults with an extreme autism syndrome. Although not out of phase, the serum melatonin levels differed from normal in amplitude and mesor. Marginal changes in diurnal rhythms of serum TSH and possibly prolactin were also recorded. Subjects with seizures tended to have an abnormal pattern of melatonin correlated with EEG changes. In others, a parallel was evidenced between thyroid function and impairment in verbal communication. There appears to be a tendency for various types of neuroendocrinological abnormalities in autistics, and melatonin, as well as possibly TSH and perhaps prolactin, could serve as biochemical variables of the biological parameters of the disease.
Effects of melatonin and thyroxine replacement on thyrotropin, luteinizing hormone, and prolactin in male hypothyroid hamsters
Endocrinology (USA), 1985, 117/6 (2402-2407)
The effects of daily evening melatonin injections on plasma and pituitary levels of TSH, LH, and PRL in hypothyroid hamsters maintained under a 14-h light, 10-h dark photoperiod were investigated. Circulating levels of thyroid hormones were monitored, and testicular weights were recorded. Thiourea-induced increases in serum and pituitary TSH were significantly reduced by melatonin injections. Control hamsters, not receiving thiourea, responded to daily evening melatonin injections with a decrease in serum Tsub 4. Serum Tsub 3 levels were decreased by thiourea and increased by Tsub 4 replacement. The pituitary PRL content was significantly reduced below control values in hamsters receiving melatonin injections; the sensitivity to melatonin was inhibited by thiourea and restored by Tsub 4 replacement. Tsub 4 replacement injections were associated with a significant decrease in serum PRL and a significant increase in serum LH. Melatonin-induced testicular involution was attenuated by thiourea administration; this attenuation was reversed by Tsub 4 replacement. Similarly, a melatonin-induced decrease in serum LH was prevented by thiourea administration and restored by Tsub 4 replacement. The data suggest that melatonin injections increase the sensitivity of the pituitary to Tsub 4/Tsub 3 feedback inhibition of TSH. Furthermore, these data show that thyroid status may influence melatonin-induced changes in release of PRL and LH from the hamster pituitary. The data showing an interaction of thyroid hormones in the control of testicular size are interpreted as evidence that thyroid hormones play a major role in the mechanism regulating gonadal cycles in the hamster.
Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study
Archives of Dermatological Research (Germany), 1996, 288/9 (522-526)
Oxygen-centred free radicals play an important role in the pathogenesis of acute and chronic UV-induced skin damage as well as in skin aging. In this double-blind randomized study the efficacy of topicacetyl-5-methoxyt ryptamine), a potent free radical scavenger, in the suppression of UV-induced erythema was assessed. A group of 20 healthy volunteers were irradiated with 0.099 J/cm2 UVB on four 5-cm2 areas on the lower back and topically treated with various concentrations of melatonin (0.05, 0.1, 0.5%) in a nanocolloid gel as carrier or with carrier alone. The UV-induced erythema was examined 8 and 24 h after irradiation by visual scoring and chromametry. A distinct dose response relationship was observed between the topical dose of melatonin and the degree of UV-induced erythema. Significant differences (P < 0.05) were found in redness (chromameter a(*)-value and visual scoring) 8 h after irradiation between the areas treated with melatonin at 0.5% and those treated with melatonin at 0.05% or with the carrier. These results might open a new approach in the prevention and control of free radical-influenced skin diseases.
Melatonin reduces mortality from Aleutian disease in mink (Mustela vison).
Department of Biology, Utah State University, Logan 84322-5305, USA.
J Pineal Res (DENMARK) Nov 1996, 21 (4) p214-7
Aleutian disease (AD) results from a persistent parvoviral infection that results in marked hypergammaglobulinemia and immune complex mediated lesions of the kidney, liver, lungs and, arteries. Melatonin protecemi strain an d a demi/dark crossed strain of mink from AD. The biogenic amine also afforded protection against other non-diagnosed diseases naturally found on mink farms when it was available from a subcutaneously-placed reservoir. Some genetic strains of mink apparently differed in the resistance of mink to the virus and in the protective ability of melatonin. The demi strain was the most resistant followed by pastels, mahogany, darks, and those strains with the double recessive Aleutian gene. The protective action of melatonin appeared to result from melatonin's ability to scavenge free radicals, but it could also be due to the induction of antioxidant enzymes or to the modulation of immunity. Melatonin also protected mink against distemper.
Gastroprotective activity of melatonin and its precursor, L-tryptophan, against stress-induced and ischaemia-induced lesions is mediated by scavenge of oxygen radicals.
Konturek PC; Konturek SJ; Brzozowski T; Dembinski A; Zembala M; Mytar B; Hahn EG
Dept. of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
Scand J Gastroenterol (NORWAY) May 1997, 32 (5) p433-8
BACKGROUND: Melatonin, a pineal hormone that is biosynthesized from L-tryptophan, is known to scavenge oxygen free radicals and to be present in the gut, but little is known about the role of this hormone and its precursor, L-tryptophan, in protecting the gastric mucosa from damage accompanied by increase in the generation of oxygen radicals. METHODS: This study was designed to determine the effects of melatonin and L-tryptophan on the formation of acute gastric lesions induced by stress and ischaemia reperfusion and, for comparison, by topical irritants such as 100% ethanol or acidified acetylsalicylic acid. RESULTS: It was found that pretreatment with melatonin in doses ranging from 1.2 to 10 mg/kg dose-dependently reduced the stress-induced gastric lesions and was accompanied by a reduction in blood-free radicals and by attenuation of the fall in gastric blood flow. L-tryptophan applied intragastrically in doses ranging from 1 to 100 mg/kg also reduced dose-dependently the lesions induced by stress; this effect too was accompanied by a rise in gastric blood flow. Pretreatment with indomethacin, to block the biosynthesis of prostaglandins, significantly augmented the lesions produced by stress and completely abolished the protective effects of melatonin or L-tryptophan. Both melatonin and tryptophan reduced the formation of acute gastric lesions provoked by ischaemia reperfusion; this was accompanied by an increase in gastric blood flow. In contrast, melatonin and L-tryptophan failed to influence acute gastric lesions induced by topical irritants such as 100% ethanol or acidified aspirin. CONCLUSIONS: Melatonin and L-tryptophan protect the gastric mucosa from damage by stress and ischaemia reperfusion, and this action is mediated, at least in part, by the limitation in the free radicals, the stimulation of mucosal generation of PG and by the increase in gastric blood flow.
Melatonin: media hype or therapeutic breakthrough?
Manhattan College, Riverdale, N.Y., USA.
Nurse Pract (UNITED STATES) Feb 1997, 22 (2) p66-7, 71-2, 77
Currently available as a dietary supplement, the pineal hormone melatonin is portrayed by the media as a formidable weapon against disease and aging. Accordingly, primary health care providers should be cognizant of which of its proposed uses are supported by biomedical research and which are, as yet, unproven. Melatonin entrains circadian rhythms and, thus, can treat jet lag, delayed sleep phase syndrome, and sleep disorders in the blind and in some neurologically impaired children. By virtue of its hypnotic effect, melatonin can mitigate insomnia in the elderly. Reductions in melatonin secretion have been associated with many disorders, including cardiovascular disease, Alzheimer's, diabetes, SIDS, and aging; however, melatonin's role in their athophysiology is unproven. Preliminary studies suggest a possible adjuvant therapeutic role for melatonin in cancer therapy. Melatonin secretion is reduced by alcohol, caffeine, and some commonly prescribed drugs. Since tolerance, fatigue, and other side effects have been reported, melatonin use on consecutive nights should be avoided and only the lowest effective hypnotic dose should be taken. (75 Refs.)
Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin.
Lissoni P; Pittalis S; Ardizzzzoni F; Maestroni GJ; Zubelewicz B; Braczkowski R
Division of Radiation Oncology, S. Gerardo Hospital, (Milan), Italy.
Support Care Cancer (GERMANY) Jul 1996, 4 (4) p313-6
Hypotension is a frequent side-effect of cancer biotherapies with cytokines. Cytokine-induced hypotension would mainly depend on the stimulation of nitric oxide (NO) production, which represents the most effective endogenous vasodilator. Moreover, it has been proven that both biological activity and toxicity of cytokines are influenced by the psychoneuroendocrine system, in particular by the pineal hormone melatonin. To investigate the possible modulatory effect of melatonin on cytokine cardiovascular toxicity, we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis-factor -alpha(TNF)-induced hypotension in advanced cancer patients. The study included 116 patients with advanced solid tumour, for whom no effective standard anticancer therapy was available, who underwent cancer biotherapy with IL-2 (3 x 10(6) IU/ day s.c. every day, 6 days/week for 4 weeks) or with TNF (0.75 mg/day i.v. for 5 days) as compassionate treatment for their disease. Patients were randomized to be treated with or without a concomitant melatonin administration (40 mg/day orally in the evening, starting 7 days prior to cytokine injection). The occurrence of hypotension was significantly less frequent in patients concomitantly treated by melatonin than in those who received the cytokine alone, during either IL-2: or TNF immunotherapy (IL-2; 11/45 versus 2/46, P < 0.05; TNF: 10/23 versus 1/12, P < 0.01). This study shows that melatonin may prevent hypotension occurring during cancer immunotherapy with IL-2 or TNF. Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells, we suggest that melatonin may prevent cytokine-induced hypotension by inhibiting NO production, which plays an essential role in inducing hypotension during IL-2 and TNF biotherapies.
Mechanisms of action of ECT in Parkinson's disease: possible role of pineal melatonin.
Int J Neurosci. 1990 Jan. 50(1-2). P 83-94
Recent clinical studies have suggested that electroconvulsive therapy (ECT) may be efficacious in the therapy of Parkinson's disease (PD). However, the mechanisms of action of ECT in PD are largely unknown. PD may be associated with reduction in the secretory activity of pineal melatonin, and the therapeutic efficacy of ECT in PD may be associated with an effect on the secretory activity of pineal melatonin. Further studies involving analysis of plasma melatonin levels and circadian release prior to and following ECT are needed more precisely to determine the role of pineal melatonin in PD and in the therapeutic efficacy of ETC in PD.
Pineal melatonin functions: possible relevance to Parkinson's disease.
Int J Neurosci. 1990 Jan. 50(1-2). P 37-53
Barbeau hypothesized that Parkinson's disease is associated with hypothalamic deficiency of the specialized neuroendocrine cell system (A.P.U.D.) and that the degeneration of brainstem monoaminergic neurons is secondary to progressive functional loss of this cell system in the disease. The pineal gland meets criteria of the A.P.U.D. cell system and it is possible that dysfunction of the pineal gland may be associated with the pathophysiology and clinical manifestations of Parkinson's disease. Since the role of pineal melatonin in humans remains enigamatic, it is currently unclear which of the symptoms of Parkinson's disease may be associated with deregulation of the secretory activity of pineal melatonin. This review summarizes evidence linking possible alterations of pineal melatonin functions with the clinical manifestations of Parkinson's disease.
Locus coeruleus-pineal melatonin interactions and the pathogenesis of the "on-off" phenomenon associated with mood changes and sensory symptoms in Parkinson's disease.
Int J Neurosci. 1989 Nov. 49(1-2). P 95-101
The "on-off" phenomenon has been reported to occur in more than 50% of patients with Parkinson's disease after 5 years of treatment with levodopa. Several recent studies have reported an association between the "on-off" phenomenon, concurrent mood changes and sensory symptoms in patients with Parkinson's disease. In these reports, "off" was associated with exacerbation of depression, anxiety and sensory symptoms, while "on" was accompanied by normalization of mood with occasional elation and attenuation in the severity of the sensory symptoms. These observations suggest that the biological mechanisms of the "on-off" interact with mechanisms regulating mood and sensory functions. The "on-off" phenomenon may be related to primary degenerative changes in the locus coeruleus (LC). The emergence of mood changes and sensory symptoms associated with the "on-off" may be facilitated by deregulation of LC-pineal melatonin functions. Administration of noradrenergic agents may be beneficial in attenuating the severity of the motor dyskinesias of the "on-off" while serotonergic drugs alone or in combination with melatonin-release enhancing agents may be useful in the management of the mood changes and sensory symptoms.
Pineal melatonin and sensory symptoms in Parkinson disease.
Ital J Neurol Sci. 1989 Aug. 10(4). P 399-403
Sensory symptoms have been reported in 40-60% of patients with Parkinson's disease, and in at least 10% of patients these symptoms precede the onset of the motor disorder. The pathophysiology of these symptoms remains unknown. Diminished brain serotonin concentration has been reported to be associated with sensory symptoms. Serotonin metabolism is regulated by pineal melatonin. The secretory activity of the pineal gland may be diminished in Parkinson's disease. In experimental animals pineal melatonin has been shown to exert analgesic effects by interacting with opiate receptors. In addition, since opioid peptides mediate the analgesic effects of melatonin, decreased opioid peptide functions in Parkinson's disease may be associated with disruption of the "fine-tuning" pain modulatory functions of melatonin and possibly indirectly facilitate the emergence of sensory symptoms.
[Neuroendocrine and psychopharmacologic aspects of the pineal function. Melatonin and psychiatric disorders]
Acta Psiquiatr Psicol Am Lat. 1989 Jan-Jun. 35(1-2). P 71-9
The development of psychiatric thought has always been in close association with the pineal gland. The importance of a relationship between pineal, and mental functions was stressed by Descartes when he placed the seat of rational thought as well as the confluence of body and soul in this organ (Cf. Descartes, L'Homme, 1664). His writings exerted such a strong influence that, quite soon indeed, physicians started regarding this gland as being the source of many mental disorders. In an attempt to find and explain a possible link between mental abnormalities, and the discovery of calcified pineals in necroptic studies, many theories were put forward during the 18th, and the 19th century. Afterwards, the importance of the gland went almost unnoticed until 1920, when Becker treated psychotic patients with pineal extracts. An up-to-1950 review by Kitay and Altschule (1954) reported 17 cases where pineal extracts were successfully injected to psychotic patients. In the present review, the author tries and summarizes several reports dealing with the influence of the pineal function on affective disorders, schizophrenia, sleep cycle, Parkinson disease, etc., as a contribution to future research work in this field.
Studies on the antiinflammatory, immunoregulatory, and analgesic actions of melatonin
Drug Development Research (USA), 1996, 39/2 (167-173)
In order to develop me(atonin (MT) as a potential new drug for the treatment of diseases with inflammation, pain, and abnormal immune responses, the effects and mechanisms of MT on inflammation, immunoregulation, and nociception were studied systematically. MT (40-160 mg/kg, ip) had significant analgesic effects in the hot-plate, writhing, and tail-flick models, with a marked dose- and time-dependence. The onset of its analgesia about 30-60 min after ip, was slower than that of pethidine, but the duration was longer (about 1.5-2 h). The analgesia was also induced by icy MT (0.25 mg/kg) injection. A lower dose of MT (10 mg/kg) could enhance the analgesic effect of pethidine, which was blocked by naloxone (10 mg/kg). MT (100 mg/kg, ip) decreased the content of beta-endorphin in the hypothalamus and pituitary. The analgesia of MT could be attenuated by pretreatment with reserpine (30 mg/kg, ip) or phentolamine (10 mg/kg, ip). CaCl2 (230 mg/kg) could antagonize the analgesia of MT. EGTA and verapamil had opposite effects to CaCl2. No tolerance and dependence to MT was found in mice. Further studies showed that MT could enhance the functions of T and B lymphocytes and macrophages in vitro and in adjuvant arthritis, and inhibit the disturbance of immune cells. MT could inhibit the swelling of hindpaw induced by carrageenin and complete Freund's adjuvant. These factors suggest that MT possesses marked antiinflammatory, immunoregulatory, and analgesic effects which may be related to the system of opiate, monoamine, and Ca2+ modulation.
Melatonin effects on behavior: Possible mediation by the central GABAergic system
Neuroscience and Biobehavioral Reviews (United Kingdom), 1996, 20/3 03-412)
The best described function of the pineal hormone melatonin is to regulate seasonal reproduction, with its daily production and secretion varying throughout the seasons or the photoperiod. Additionally, a number of behavioral effects of the hormone have been found. This review describes the effects of melatonin in rodent behavior. We focus on: (a) inhibitory effects (sedation, hypnotic activity, pain perception threshold elevation, anti- convulsive activity, anti-anxiety effects): and (b) direct effects on circadian rhythmicity (entrainment, resynchronization, alleviation of jet- lag symptoms, phase-shifting). Most of these effects are clearly time- dependent, with a peak of melatonin activity during the night. One of the possible mechanisms of action for melatonin in the brain is the interaction with the GABAergic system, as suggested by neurochemical and behavioral data. Finally, some pineal hormone effects might be candidates as putative therapies for several human disorders.
Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus
Cephalalgia (Norway), 1997, 17/4 (511-517)
The plasma melatonin profile was significantly disturbed (phase-shift of the maximum melatonin level) in four out of six female sufferers from status migrainosus, compared with nine healthy controls. The number of secretion peaks was similar in both groups. A nocturnal 20 pg melatonin infusion (from 21.00 to 01.00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak. During infusion, the episodes of secretion were reinforced and the endogenous plasma profile was phase-advanced in two patients displaying a phase-delay. These data suggest impaired pineal function in migraine. In the absence of side effects of melatonin infusion, the relief of certain migraine symptoms described by our patients might support a controlled trial of melatonin in migraine.
Nocturnal melatonin excretion is decreased in patients with migraine without aura attacks associated with menses
Cephalalgia (Norway), 1995, 15/2 (136-139)
Nocturnal melatonin excretion was studied throughout a complete menstrual cycle in 10 women with migraine without aura attacks associated with menses and 9 women controls. Urine melatonin was determined by radioimmunoassay. The mean nocturnal melatonin excretion throughout the cycle was significantly lower in the migraine patients than in controls. In the control group, melatonin excretion increased significantly from the follicular to the luteal phase, whereas no difference was observed in the migraine group. Results are discussed in view of the role of the pineal gland in the organization of biological rhythms and homeostasis in relation to environmental conditions.
Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine
CEPHALALGIA (Norway), 1994
Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in 12 migraine without aura patients compared to 8 healthy controls. Normal increases in urinary melatonin excretion during the luteal phase was less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.
Nocturnal plasma melatonin levels in migraine: A preliminary report
Headache (UNITED STATES) Apr 1989, 29 (4) p242-5
We determined by radioimmunoassay plasma melatonin levels on blood samples drawn at 11 p.m. in migraine patients and control subjects. Ninety-three cephalalgic outpatients (75 females, 18 males) were compared to a control group (24 females, 22 males) matched according to age. Patients were divided into subgroups presenting common migraine (n = 38); ophthalmic migraine (n = 12); and tension headache associated with ophthalmic or common migraine (n = 24), and associated depressive status (n = 19). Statistical analysis revealed a decrease in plasma melatonin levels for the entire migraine population, compared to the control one, and a heterogeneity in both controls and patients; this heterogeneity was found mainly in the depressive and tension headache subgroups. When the migraine population - from which the depressive patients were excluded - was divided into male and female subgroups, a decrease in plasma melatonin levels was observed only for the female subgroups. Results are discussed with reference to the role of the pineal gland in the synchronization of the organism with the environmental conditions.
The influence of the pineal gland on migraine and cluster headaches and effects of treatment with picoTesla magnetic fields.
Int J Neurosci (ENGLAND) Nov-Dec 1992, 67 (1-4) p145-71
For over half a century the generally accepted views on the pathogenesis of migraine were based on the theories of Harold Wolff implicating changes in cerebral vascular tone in the development of migraine. Recent studies, which are based on Leao's concept of spreading depression, favor primary neuronal injury with secondary involvement of the cerebral circulation. In contrast to migraine, the pathogenesis of cluster headache (CH) remains entirely elusive. Both migraine and CH are cyclical disorders which are characterised by spontaneous exacerbations and remissions, seasonal variability of symptoms, and a relationship to a variety of environmental trigger factors. CH in particular has a strong circadian and seasonal regularity. It is now well established that the pineal gland is an adaptive organ which maintains and regulates cerebral homeostasis by "fine tuning" biological rhythms through the mediation of melatonin. Since migraine and CH reflect abnormal adaptive responses to environmental influences resulting in heightened neurovascular reactivity, I propose that the pineal gland is a critical mediator in their pathogenesis. This novel hypothesis provides a framework for future research and development of new therapeutic modalities for these chronic headache syndromes. The successful treatment of a patient with an acute migraine attack with external magnetic fields, which acutely inhibit melatonin secretion in animals and humans, attests to the importance of the pineal gland in the pathogenesis of migraine headache. (242 Refs.)
Is migraine due to a deficiency of pineal melatonin?
Ital J Neurol Sci (ITALY) Jun 1986, 7 (3) p319-23
Recent clinical observations favor the theory that migraine is caused by a primary injury of cerebral neurons with secondary involvement of intracranial and extracranial blood vessels. The primary injury is attributed to disruption of cerebral neurotransmitters and particularly the neuroadrenergic and serotonergic systems. These theories have not explained the importance of environmental factors, which so frequently trigger migraine. The author suggests that the pineal gland, which is outside the CNS unprotected by blood brain barrier and sensitive to external stimuli, could act as the intermediate causative factor of migraine, via a derangement of melatonin. (47 Refs.)
Melatonin in humans physiological and clinical studies.
J Neural Transm Suppl (AUSTRIA) 1978, (13) p289-310
Studies are reported of the variation of melatonin in serum, plasma urine and cerebrospinal fluid in normal subjects and in patients with various diseases. The diurnal variation of plasma and urine melatonin found in healthy controls on a regular dark-sleep pattern persisted when the subjects slept in light. The effect of sleep deprivation and of rapid light exposure at night is reported. There was a correlation between melatonin in morning urine and plasma at 2 a.m. Four hours of extended darkness in the morning as well as a 9-hour shift of sleep and activity cycles following travel affected the melatonin rhythm. The night increase in plasma melatonin preceeded both the cortisol and prolactin rise. A single oral dose of 4.3 X 10(5) nmol of melatonin given to a 44-year-old healthy male gave a peak plasma value of 624 nmol/l after 30 min. Plasma melatonin was not affected by electroconvulsive therapy, TRH-injection, L-Dopa or bromoergocryptine orally. Patients with alcoholism, migraine, postoperative pinealoma, panhypopituitarism, hereditary dystonia and schizophrenics on propranolol exhibited a decreased amplitude of their diurnal rhythm of melatonin. Two patients with pituitary tumors had occasional high levels of plasma melatonin. The change in melatonin secretion in human is apparently controlled by a mechanism which is at least party influenced by environmental lighting conditions, drugs and different disease states. (27 refs.)
Treatment of circadian rhythm disorders - Melatonin
Chronobiology International (USA), 1997, 14/2 (185-204)
Melatonin has clear acute and delayed effects on sleep and circadian rhythms. Decrements in core temperature and alertness have been found at different times of day following low pharmacological and physiological doses of melatonin. When correctly timed, melatonin induces both phase advances and phase delays of the circadian system in humans. When timed to advance, the decrement in temperature and alertness and the degree of shift are closely related to dose. In both stimulation and field studies, correctly timed melatonin can alleviate some of the problems of shiftwork and jet lag, notably enhancing sleep and alertness and hastening adaptation of rhythms to the imposed schedule. Performance effects and changes in sleep architecture need to be fully evaluated. The optimization of dose and formulation is also an area that requires furter work. Whether or not recently developed melatonin analogs will prove more or less useful than melatonin in adapting to phase shift remains to be seen. If incorrectly timed, melatonin has the potential to induce deleterious effects. While short-term studies indicate that it has very low toxicity, there are no long-term safety data. All of the studies reported here concern healthy adult volunteers and the use of a preparation licensed for human experimental use and available on a named patient basis on prescription. There are not data on uncontrolled preparations available over the counter in some countries. Its effects in pregnancy, interaction with other medications, and many other considerations remain to be addressed. Thus, while melatonin is useful in well-controlled conditions, the indiscriminate use of unlicensed preparations is not advisable.
The Mel(1a) melatonin receptor gene is expressed in human suprachiasmatic nuclei
NeuroReport (United Kingdom), 1997, 8/1 (109-112)
The pineal hormone melatonin influences circadian rhythmicity in many vertebrate species. The circadian effects of melatonin in humans have led to its use to treat jet lag and circadian-based sleep disorders. Melatonin is thought to influence circadian rhythmicity by acting in the suprachiasmatic nuclei (SCN). recent cloning of two melatonin receptor subtypes with high affinity for melatonin allows molecular analysis of melatonin receptors in human SCN. We report that Mel(1a) receptor mRNA is detectable in neonatal human SCN by in situ hybridization. Mel(1b) and melatonin-related receptor mRNAs were not detected. The presence of Mel(1a) receptor mRNA in human SCN supports the hypothesis that the Mel(1a) receptor is responsible for the circadian effects of melatonin in humans.
Circadian sleep-wake disorders
Revue du Praticien (France), 1996, 46/20 (2442-2447)
The circadian system is synchronized on 24-hour by the light-dark synchronizer and by the social time cue. The circadian rhythm sleep disorders share a common underlying chronobiological basis. These disorders may be due to either jet-lag, shift-work or to lesions of the peripheral visual pathway. The delayed sleep phase syndrome, the advanced sleep phase syndrome, the non 24-hour syndrome as well as the irregular sleep-wake patterns are described. Therapeutic approaches, in particular with melatonin and (or) bright light, are presented.Melatonin and jet lag
Netherlands Journal of Medicine (Netherlands), 1996, 49/4 (164-166)
Jet lag is an ill-defined phenomenon resulting from rapid transmeridional flight and is considered to be due to desynchronization of circadian rhythms. The role of the pineal gland hormone, melatonin, in the synchronization of biological rhythms has raised interest in its use to alleviate jet lag. Indeed, recent studies support the use of this well-tolerated drug as a remedy for jet lag on long-haul flights.