Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin.

AIM Since melatonin is antioxidant and has some anti-inflammatory actions, we have tested it as adjunctive treatment in patients with rheumatoid arthritis, to determine whether it can improve patients' symptoms. METHODS A total of 75 patients were allocated randomly to receive melatonin 10 mg at night in addition to ongoing medication, or a placebo of identical appearance. Monthly blood samples were taken and disease severity assessed over 6 months, plasma being analysed for inflammatory indicators [C-reactive protein, erythrocyte sedimentation rate (ESR), neopterin], proinflammatory cytokines [interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha], lipid peroxidation products and the kynurenine pathway metabolites of tryptophan. RESULTS An increase of ESR (two-way anova F((1,127)) = 5.24, P = 0.024) and neopterin concentrations (F((1,136)) = 4.64, P = 0.033) was observed in treated patients compared with controls, reflected also in a significant trend for both to decline in placebo-treated patients (P = 0.022), but not the melatonin-treated group. Peroxidation products showed a significant trend to decrease in placebo- but not melatonin-treated patients. These results suggest a proinflammatory action, but there were no significant effects of melatonin treatment on clinical assessments of patient symptoms or the concentrations of three proinflammatory cytokines, IL-1beta, IL-6 and TNF-alpha. Melatonin significantly increased plasma kynurenine concentrations (F((1,124)) = 4.24, P = 0.041), again suggesting proinflammatory activity. CONCLUSION A daily dose of 10 mg melatonin shows a slowly developing antioxidant profile in patients with arthritis and increases the concentrations of some inflammatory indicators, but these effects are not associated with any change of proinflammatory cytokine concentrations or clinical symptoms.

[1]  A. Westergren.  Studies of the Suspension Stability of the Blood in Pulmonary Tuberculosis1 , 2009 .

[2]  T. Stone,et al.  Blood 5‐hydroxytryptamine, 5‐hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury , 2006, Journal of neurochemistry.

[3]  T. Stone,et al.  Tryptophan metabolism and oxidative stress in patients with chronic brain injury , 2006, European journal of neurology.

[4]  A. Koçyiğit,et al.  Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. , 2005, Clinical biochemistry.

[5]  G. Maestroni,et al.  The melatonin-cytokine connection in rheumatoid arthritis , 2005, Annals of the rheumatic diseases.

[6]  D. Fuchs,et al.  Tryptophan degradation in patients with gynecological cancer correlates with immune activation. , 2005, Cancer letters.

[7]  T. Stone,et al.  Tryptophan metabolism and oxidative stress in patients with Huntington's disease , 2005, Journal of neurochemistry.

[8]  G. Ortiz,et al.  Effects of melatonin on plasma levels of TNF-α, IL-1 and IL-6 in mice after lipopolysaccharide administration , 2005 .

[9]  G. Maestroni,et al.  Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison , 2005, Annals of the rheumatic diseases.

[10]  G. Amarante-Mendes,et al.  Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release , 2004, Journal of Neuroimmunology.

[11]  S. Oikawa,et al.  Oxidative DNA damage induced by a melatonin metabolite, 6-hydroxymelatonin, via a unique non-o-quinone type of redox cycle. , 2004, Biochemical pharmacology.

[12]  T. Stone,et al.  Tryptophan Loading Induces Oxidative Stress , 2004, Free radical research.

[13]  H. C. Mehta,et al.  Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[14]  D. Fuchs,et al.  Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. , 2003, The Journal of rheumatology.

[15]  H. Pons,et al.  Melatonin Increases Interleukin-1β and Decreases Tumor Necrosis Factor Alpha in the Brain of Mice Infected with the Venezuelan Equine Encephalomyelitis Virus , 2003, Neurochemical Research.

[16]  G. Maestroni,et al.  Melatonin in rheumatoid arthritis: a disease-promoting and modulating hormone? , 2002, Clinical and experimental rheumatology.

[17]  Josep M. Guerrero,et al.  Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C , 2002, Journal of neuroscience research.

[18]  R. Reiter,et al.  A novel role for melatonin: regulation of the expression of cell adhesion molecules in the rat hippocampus and cortex , 2002, Neuroscience Letters.

[19]  G. Maestroni,et al.  Melatonin in Rheumatoid Arthritis , 2002 .

[20]  G. Maestroni,et al.  Melatonin Serum Levels in Rheumatoid Arthritis , 2002, Annals of the New York Academy of Sciences.

[21]  H. Canatan,et al.  Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin‐induced diabetes mellitus , 2002, Journal of pineal research.

[22]  F. Polat,et al.  Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis , 2002, Rheumatology International.

[23]  B Claustrat,et al.  Daytime 50 Hz magnetic field exposure and plasma melatonin and urinary 6‐sulfatoxymelatonin concentration profiles in humans , 2001, Journal of pineal research.

[24]  S. Ozgoçmen,et al.  The relationships between plasma and erythrocyte antioxidant enzymes and lipid peroxidation in patients with rheumatoid arthritis , 2001 .

[25]  E. El-Bassiouni,et al.  Antioxidants as Adjuvant Therapy in Rheumatoid Disease , 2001, Arzneimittelforschung.

[26]  J. A. Mcnulty,et al.  Assessment of melatonin's ability to regulate cytokine production by macrophage and microglia cell types , 2001, Journal of Neuroimmunology.

[27]  S. Weintraub,et al.  Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. , 2000, Free radical biology & medicine.

[28]  G. Hasçelik,et al.  Melatonin modulates mesenteric blood flow and TNFalpha concentrations after lipopolysaccharide challenge. , 2000, The European journal of surgery = Acta chirurgica.

[29]  R. Reiter,et al.  Melatonin and Its Relation to the Immune System and Inflammation , 2000, Annals of the New York Academy of Sciences.

[30]  M. Cutolo,et al.  Melatonin Influences Interleukin‐12 and Nitric Oxide Production by Primary Cultures of Rheumatoid Synovial Macrophages and THP‐1 Cells a , 1999, Annals of the New York Academy of Sciences.

[31]  J. Williams,et al.  EFFECT OF MELATONIN ON ACTIVATED MACROPHAGE TNF, IL‐6, AND REACTIVE OXYGEN INTERMEDIATES , 1998, Shock.

[32]  H. Wong,et al.  Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκB activation , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  J. Arendt.  Safety of Melatonin in Long-Term Use(?) , 1997, Journal of biological rhythms.

[34]  P. Cowen,et al.  Case-control study of evening melatonin concentration in primary insomnia , 1996, BMJ.

[35]  M. Roselli,et al.  Modulation of cytokine production from TH2-lymphocytes and monocytes by the pineal neurohormone melatonin. , 1996, Oncology reports.

[36]  P. Beyne,et al.  Determination of tryptophan and its kynurenine pathway metabolites in human serum by high-performance liquid chromatography with simultaneous ultraviolet and fluorimetric detection. , 1996, Journal of chromatography. B, Biomedical applications.

[37]  S. Barni,et al.  Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. , 1995, Oncology.

[38]  R. Reiter,et al.  A review of the evidence supporting melatonin's role as an antioxidant , 1995, Journal of pineal research.

[39]  L. Paulesu,et al.  Inhibitory effect of melatonin on production of IFNγ or TNFα in peripheral blood mononuclear cells of some blood donors , 1994 .

[40]  X. Martin.  New insights into the autonomous regulation of intraocular pressure , 1994 .

[41]  R. Holmdahl,et al.  Pinealectomy ameliorates collagen II‐induced arthritis in mice , 1993, Clinical and experimental immunology.

[42]  J. S. Chairman..  ICSH recommendations for measurement of erythrocyte sedimentation rate , 2004 .

[43]  R. Holmdahl,et al.  The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice , 1992, Journal of Neuroimmunology.

[44]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[45]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[46]  D. Cardinali,et al.  Melatonin, 5-methoxytryptamine and some of their analogs as cyclo-oxygenase inhibitors in rat medial basal hypothalamus , 1987, Brain Research.

[47]  M. Pawlikowski,et al.  Melatonin Inhibits Prostaglandin E Release From the Medial Basal Hypothalamus of Pinealectomized Rats , 1984, Journal of pineal research.

[48]  R. Kelly,et al.  N-acetyl-5-methoxy kynurenamine, a brain metabolite of melatonin, is a potent inhibitor of prostaglandin biosynthesis. , 1984, Biochemical and biophysical research communications.

[49]  P. Cowen,et al.  Direct radioimmunoassay for melatonin in plasma. , 1983, Clinical chemistry.

[50]  D. Cardinali,et al.  Melatonin blocks in vitro generation of prostaglandin by the uterus and hypothalamus. , 1980, European journal of pharmacology.

[51]  M. Nazıroğlu,et al.  Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis , 2004, Cell biochemistry and function.

[52]  T. Stone,et al.  Kynurenine and neopterin levels in patients with rheumatoid arthritis and osteoporosis during drug treatment. , 2003, Advances in experimental medicine and biology.

[53]  D. Acuña-Castroviejo,et al.  Mitochondrial regulation by melatonin and its metabolites. , 2003, Advances in experimental medicine and biology.

[54]  G. Maestroni,et al.  Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. , 2002, Annals of the New York Academy of Sciences.

[55]  J. Fourtillan,et al.  Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. , 2000, Biopharmaceutics & drug disposition.

[56]  İ. Durak,et al.  Oxidant/antioxidant status of plasma samples from patients with rheumatoid arthritis , 1999, Rheumatology International.

[57]  C. Chignell,et al.  Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. , 1997, Free radical biology & medicine.

[58]  R. Reiter,et al.  Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. , 1994, Life sciences.

[59]  L. Paulesu,et al.  Inhibitory effect of melatonin on production of IFN gamma or TNF alpha in peripheral blood mononuclear cells of some blood donors. , 1994, Journal of pineal research.

[60]  J. Oosthuizen,et al.  Melatonin Levels are Decreased in Rheumatoid Arthritis , 1992, Journal of basic and clinical physiology and pharmacology.

[61]  K. Shibata,et al.  Fluorimetric micro-determination of kynurenic acid, an endogenous blocker of neurotoxicity, by high-performance liquid chromatography. , 1988, Journal of chromatography.