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      Endotoxin-Induced Inflammation Suppresses the Effect of Melatonin on the Release of LH from the Ovine Pars Tuberalis Explants—Ex Vivo Study

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          Abstract

          The secretion of the hormone melatonin reliably reflects environmental light conditions. Among numerous actions, in seasonal breeders, melatonin may regulate the secretion of the gonadotropins acting via its corresponding receptors occurring in the Pars Tuberalis ( PT). However, it was previously found that the secretory activity of the pituitary may be dependent on the immune status of the animal. Therefore, this study was designed to determine the role of melatonin in the modulation of luteinizing hormone (LH) secretion from the PT explants collected from saline- and endotoxin-treated ewes in the follicular phase of the oestrous cycle. Twelve Blackhead ewes were sacrificed 3 h after injection with lipopolysaccharide (LPS; 400 ng/kg) or saline, and the PTs were collected. Each PT was cut into 4 explants, which were then divided into 4 groups: I, incubated with ‘pure’ medium 199; II, treated with gonadotropin-releasing hormone (GnRH) (100 pg/mL); III, treated with melatonin (10 nmol/mL); and IV, incubated with GnRH and melatonin. Melatonin reduced ( p < 0.05) GnRH-induced secretion of LH only in the PT from saline-treated ewes. Explants collected from LPS-treated ewes were characterized by lower ( p < 0.05) GnRH-dependent response in LH release. It was also found that inflammation reduced the gene expression of the GnRH receptor and the MT1 melatonin receptors in the PT. Therefore, it was shown that inflammation affects the melatonin action on LH secretion from the PT, which may be one of the mechanisms via which immune/inflammatory challenges disturb reproduction processes in animals.

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          Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding.

          Melatonin has been shown to be produced by nonpineal cells and possess anti-inflammatory actions in animal models. In the present study, we tested the hypothesis that melatonin suppresses the expression of proinflammatory genes such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (INOS) by a common transcriptional mechanism. Melatonin but not tryptophan or serotonin inhibited lipopolysaccharide (LPS)-induced COX-2 and iNOS protein levels and promoter activities in RAW 264.7 cells in a time- and concentration-dependent manner. LPS or LPS plus interferon-gamma (IFNgamma) increased binding of all 5 isoforms of NF-kappaB to COX-2 and iNOS promoters. Melatonin selectively inhibited p52 binding without affecting p100 expression, p52 generation from p100, or p52 nuclear translocation. p52 acetylation was enhanced by LPS, which was abrogated by melatonin. Melatonin inhibited p300 histone acetyltransferase (HAT) activity and abrogated p300-augmented COX-2 and iNOS expression. HAT inhibitors suppressed LPS-induced p52 binding and acetylation to an extent similar to melatonin, and melatonin did not potentiate the effect of HAT inhibitors. These results suggest that melatonin inhibits COX-2 and iNOS transcriptional activation by inhibiting p300 HAT activity, thereby suppressing p52 acetylation, binding, and transactivation.
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            Immune-Pineal Axis: Nuclear Factor κB (NF-κB) Mediates the Shift in the Melatonin Source from Pinealocytes to Immune Competent Cells

            Pineal gland melatonin is the darkness hormone, while extra-pineal melatonin produced by the gonads, gut, retina, and immune competent cells acts as a paracrine or autocrine mediator. The well-known immunomodulatory effect of melatonin is observed either as an endocrine, a paracrine or an autocrine response. In mammals, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) blocks noradrenaline-induced melatonin synthesis in pinealocytes, which induces melatonin synthesis in macrophages. In addition, melatonin reduces NF-κB activation in pinealocytes and immune competent cells. Therefore, pathogen- or danger-associated molecular patterns transiently switch the synthesis of melatonin from pinealocytes to immune competent cells, and as the response progresses melatonin inhibition of NF-κB activity leads these cells to a more quiescent state. The opposite effect of NF-κB in pinealocytes and immune competent cells is due to different NF-κB dimers recruited in each phase of the defense response. This coordinated shift of the source of melatonin driven by NF-κB is called the immune-pineal axis. Finally, we discuss how this concept might be relevant to a better understanding of pathological conditions with impaired melatonin rhythms and hope it opens new horizons for the research of side effects of melatonin-based therapies.
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              Effect of melatonin on neuroinflammation and acetylcholinesterase activity induced by LPS in rat brain.

              Melatonin, which plays an important role in circadian rhythm regulation, is highly potent endogenous free radical scavenger and antioxidant. To determine the efficacy of melatonin in neuroinflammation induced by intracerebroventricular (i.c.v.) administration of lipopolysachcharide (LPS, 50 microg), pro-inflammatory cytokines (TNF-alpha and IL-1beta), and markers of oxidative stress (malondialdehyde and reduced glutathione) were studied in different brain regions (striatum, cerebral cortex, hippocampus and hypothalamus) of rat. To study the cholinergic intervention during neuroinflammatory conditions acetylcholinesterase (AChE) enzyme activity was taken as marker of cholinergic activity. Melatonin (5 and 10 mg/kg, p.o.) decreased the LPS induced pro-inflammatory cytokines and oxidative stress in different brain regions. It was also found to inhibit the LPS induced increase in AChE activity. These results suggest the therapeutic potential of melatonin for neuroinflammation which is an integral part of neurodegenerative disorders. Copyright (c) 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                MDPI
                1420-3049
                10 November 2017
                November 2017
                : 22
                : 11
                : 1933
                Affiliations
                The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3 Street, 05-110 Jabłonna, Poland; k.wojtulewicz@ 123456ifzz.pl (K.W.); d.tomaszewska@ 123456ifzz.pl (D.T.-Z.)
                Author notes
                [* ]Correspondence: a.herman@ 123456ifzz.pl ; Tel.: +48-22-765-3300
                Author information
                https://orcid.org/0000-0002-4538-8761
                https://orcid.org/0000-0002-2619-4638
                https://orcid.org/0000-0003-4116-6309
                Article
                molecules-22-01933
                10.3390/molecules22111933
                6150294
                29125559
                e6d35fef-16ed-4e6f-8a75-d755843c0689
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 September 2017
                : 07 November 2017
                Categories
                Article

                melatonin,lipopolysaccharide,luteinizing hormone,gnrh,melatonin receptors,pars tuberalis

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