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      Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat.

      Neuroendocrinology
      Adrenal Glands, drug effects, physiology, Adrenocorticotropic Hormone, secretion, Animals, Arginine Vasopressin, genetics, Circadian Rhythm, Corticosterone, Corticotropin-Releasing Hormone, Dexamethasone, administration & dosage, pharmacology, Glucocorticoids, Hypothalamus, Male, Melatonin, blood, Pituitary Gland, RNA, Messenger, metabolism, Rats, Rats, Wistar, Receptors, Glucocorticoid, Weight Loss

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          Abstract

          Transient exposure of rats to high doses of dexamethasone (DEX; 500 microg/day for 5 days) produced a host of symptoms that are indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, such as increased adrenocortical secretion over 24 h, blunted and prolonged secretory response to emotional stress, refractoriness of adrenocorticotropin in vitro release to stimulation with the secretagogues corticotropin-releasing hormone (CRH) and vasopressin, decreased levels of mRNA encoding type II corticosteroid receptors in the hippocampus and increased numbers of transcripts encoding CRH in the paraventricular nucleus. Daily administration of melatonin (MEL; 80 microg/kg) concomitantly with, and for 5 days after discontinuation of, glucocorticoid treatment 'normalized' most of the symptoms of impaired HPA regulation caused by the exposure to DEX. While none of the treatments used caused major shifts in circadian patterns of corticosterone secretion, MEL administration was associated with diminished overall corticosterone secretion and increased sensitivity to glucocorticoid feedback. Taken together, these findings indicate that chronic MEL treatment may protect several regulatory components of the HPA axis from glucocorticoid-induced deterioration.

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          Most cited references19

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          Regulation of pituitary ACTH secretion during chronic stress.

          Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.
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            The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response.

            The cloning of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) cDNAs provides a basis for understanding the actions of glucocorticoids in the central nervous system. Structural evidence is presented for the identity of the type I corticosteroid binding site as the MR expressed in the brain. This identification is supported by the anatomical distribution of MR mRNA, determined by in situ hybridization histochemistry, which parallels the steroid autoradiographic localization of the type I sites. An in vitro assay for MR and GR function demonstrates that these receptors respond to different levels of glucocorticoid, suggesting that together they confer a larger dynamic range of sensitivity to this hormone. These studies lead to a new hypothesis for glucocorticoid action in the central nervous system.
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              Functional pleiotropy of the neurohormone melatonin: antioxidant protection and neuroendocrine regulation.

              The pineal hormone melatonin exhibits remarkable functional versatility. Shortly after its discovery, melatonin was functionally linked to the regulation of the neuroendocrine axis, particularly to the reproductive system. However, judging from the wide variety of cellular changes that occurred following either pinealectomy, to remove the primary source of melatonin, or the exogenous administration of the indole, it was obvious that the activity of melatonin far transcended its actions on the hypothalamo-pituitary-gonadal system. Roughly 30 months ago it was discovered that melatonin is a highly efficient free radical scavenger and general antioxidant. This implied that melatonin, which is both lipophilic and hydrophilic, has effects not only in every cell but also within every subcellular compartment. These intracellular actions of melatonin, some of which are independent of any receptor interaction and some of which are mediated by nuclear receptors, have become the focus of much of the current investigation. As an antioxidant, melatonin has been shown in vitro to be a highly efficient scavenger of the very reactive and toxic hydroxyl radical. Indeed, on an equimolar basis melatonin proved significantly more efficient in neutralizing the hydroxyl radical than did the two well-known scavengers, glutathione and mannitol. Likewise, melatonin was found to also scavenge the peroxyl radical which is generated during lipid peroxidation; in this regard it was roughly twice as effective as vitamin E (alpha-tocopherol). The antioxidant activities of melatonin have been well documented in tissue homogenates and organisms as well. When rats are treated with the chemical carcinogen safrole, this agent induces the generation of free radicals which in turn extensively damage nuclear DNA; this damage is almost totally eliminated if the animals are cotreated with melatonin. Also, damage to DNA in human lymphocytes due to ionizing radiation, another treatment which is known to induce free radical formation, is greatly reduced if the cells are treated with melatonin prior to radiation. Cytosolic protein seems also to be protected from free radical damage when melatonin is present. When newborn rats are treated with a glutathione-depleting drug at birth, by 2 weeks of age the animals have cataracts. Cataracts form because oxidants damage protein in the presence of low intracellular levels of glutathione. Cataracts induced by this means are essentially prevented if the glutathione-depleted rats are supplemented with melatonin. Finally, membrane lipid peroxidation, induced either in vivo or in vitro by any of several means, all of which involve free radicals, is drastically attenuated in the presence of melatonin. Considering melatonin's ability to cross all morphophysiological barriers and to enter every cell, and all subcellular compartments, the implication is that this indole may play a very important role in the antioxidative defense system of the organism. These findings potentially have important implications for a wide variety of age-related diseases and to aging itself. Melatonin's control of reproductive physiology in photoperiodic mammals is well documented. However, the site of interaction of melatonin with the neuroendocrine axis has been especially difficult to determine. The discovery and cloning of a membrane melatonin receptor on neurosecretory cells in the hypothalamus and on hormone secreting cells of the anterior pituitary gland stimulated a great deal of investigation which has failed to prove the involvement of these receptors in the processes by which melatonin influences reproductive physiology. The recent identification of nuclear melatonin receptors as well as the nonreceptor-mediated actions of the indole are currently being examined as to their association with reproductive function.
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