To gain insight into the relationship between thymus and pineal gland during rat development, the melatonin content as well as the activity and expression of the two key enzymes for melatonin biosynthesis, i.e. N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), were studied in the thymus at fetal and postnatal stages. Moreover, melatonin-membrane receptor (MT1) expression was also analyzed. We found both the expression and activity of thymic NAT and HIOMT at 18 days of fetal life. Additionally, there is production of melatonin in the thymus as well as MT1 expression at this fetal age. These results show values higher in day-time than at night-time. The pineal gland begins to produce significant levels of melatonin around postnatal day 16, and this synthesis shows a circadian rhythm with high values during the dark period; therefore the nocturnal serum melatonin may inhibit thymic melatonin production. To document this, we report an increased melatonin content of the thymus in pinealectomized rats compared with sham-pinealectomized. In conclusion, these results show, for the first time, the presence of the biosynthetic machinery of melatonin and melatonin production in developing rat thymus and that the pineal gland may regulate this process.

Melatonin production is not restricted to the pineal gland. Several extrapineal sources of this indole such as retina, Harderian gland, and immune system are well documented. Melatonin of pineal origin is not present in the rat at early stages of development. To assess the potential capacity of local melatonin synthesis by the immature brain and to gain insight into the relationship between melatonin production by the brain (without the pineal gland) and pineal gland during rat development, the melatonin content as well as the expression and activity of the melatonin-synthesizing enzymes, N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), were studied at fetal and postnatal stages. Moreover, melatonin-membrane receptor (MT(1)) expression was also analyzed. Both, the expression and activity of NAT and HIOMT were found in the brain with significant day/night differences in enzymes activities. Additionally, melatonin content was detected in all stages showing day/night differences depending on the stage of development. The brain nocturnal melatonin content was higher than diurnal content on postnatal day 16 and in adult rats which is in accordance with the pineal melatonin synthesis. To investigate the origin of this brain melatonin, pinealectomized rats were used and we found that the developing brain produced its own melatonin. Also, MT(1) expression was detected in brain during development. These results demonstrate that, when the pineal is not yet producing melatonin, there is melatonin synthesis by the brain that could be used as protection from free radical damage and/or could exert some actions through MT(1) receptors.

The aim of this study was to determine the effects of melatonin on proinflammatory status of rats with collagen-induced arthritis (CIA). CIA was induced in male Wistar rats with an emulsion of type II collagen in Freund's Incomplete Adjuvant (C-II/FIA). For 14 days, control and pinealectomized rats received a subcutaneous injection of 100 microL melatonin (30 microg) or vehicle (saline on 1% ethanol). Levels of cytokines interleukin (IL)-1beta and IL-6 were determined in the serum, peripheral blood mononuclear cells, and joints. Levels of anti-type II collagen antibody, nitrite/nitrate, and lipid peroxidation (LPO) were determined in the serum, joints, and brain. Treatment with melatonin significantly increased the levels of IL-1beta, IL-6, nitrite/nitrate and LPO in joints. However, melatonin significantly reduced the levels of nitrite/nitrate and LPO in serum and brain. Moreover, CIA in pinealectomized rats presented significantly reduced levels of IL-1beta and IL-6, titers of anti-type II collagen antibodies, levels of nitrite/nitrate, and LPO in joints but elevated levels in serum and brain. Melatonin has been described as a proinflammatory and antioxidant agent. In a process of inflammation as CIA, melatonin acts with a markedly proinflammatory effect at local and peripheral levels maintaining its antioxidant effect only at peripheral level.

In this study, the effect of chronic administration of melatonin on MRL/MpJ-Fas lpr mice has been studied. These mice spontaneously develop an autoimmune disease that has many features resembling human systemic lupus erythematosus. In fact, histological studies showed that all female mice and most male mice exhibited glomerular abnormalities, arteritic lesions, and cellular interstitial inflammatory infiltrate ranging from mild to severe patterns.