Melatonin Role in Experimental Arthritis

Abstract

Our perception of the function of the pineal gland and its hormone melatonin has attained a new dimension during the last decade. Through melatonin, the pineal becomes a principal organ present in vertebrates involved in the control of rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can "read" the message. Melatonin acts as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of them is the circadian organization of the immune response. This review discusses melatonin role in rheumatoid arthritis. Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis are described. Immune and neuroendocrine circadian rhythms were examined in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-h organization of immune and neuroendocrine responses becomes altered. Significant effects of immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin treatment prevented alteration of the 24-h variation in hypothalamic monoamine transmitter turnover during the preclinical phase of Freund's adjuvant arthritis in rats. A comparison between the inflammatory and immune responses elicited by physiological and pharmacological doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma melatonin, augmented the inflammatory and immune response. These results should be considered in the light of recent reports that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production.

24-Hour variation in gene expression of redox pathway enzymes in rat hypothalamus: effect of melatonin treatment

“…This dose was 10 times higher than that needed to attain physiological circulating melatonin levels in pinealectomized rats. 17 Nocturnal water consumption did not differ among the experimental groups.…”

Salutary effects of melatonin combined with treadmill exercise on cartilage damage

“…Maestroni and colleagues reported that melatonin has been found to be present in synovial fluid from rheumatoid arthritis (RA) patients (79.8 ± 38.9 pg/mL) as well as healthy subjects (data not shown) . A high melatonin dose (30 μ g/mL of drinking water) caused a 50‐ to 60‐fold increase in plasma melatonin, which led to enhancement of the immune response in the experimental inflammatory arthritic rats . Synovial macrophages have high‐affinity binding sites for melatonin in RA patients, which may be a potent reason of immune‐enhancing phenomenon by exogenous melatonin .…”

“…Synovial macrophages have high‐affinity binding sites for melatonin in RA patients, which may be a potent reason of immune‐enhancing phenomenon by exogenous melatonin . It has been frequently reported the results that indicate the detrimental effect of melatonin on RA pathogenesis , whereas the previous study regarding its effect on OA has been little investigated. Moreover, a direct correlation between blood levels of melatonin and its intracellular concentrations may be erroneous, although melatonin's efficacy in vivo is also often based on the low levels (10–200 pg/mL) of melatonin in the blood .…”

Cadmium-Induced Disruption in 24-h Expression of Clock and Redox Enzyme Genes in Rat Medial Basal Hypothalamus: Prevention by Melatonin

“…Since rats drank about 20 mL/day with 90–95% of this total daily water taken up during the dark period, the melatonin dosage used provided approximately 60 μg melatonin/day. This dose was 10 timed higher than that needed to obtain physiological circulating melatonin levels in pinealectomized rats (Cardinali et al, 2004). Nocturnal water consumption did not differ among the experimental groups.…”