Dose-Dependent Anti-Inflammatory Activity of Melatonin in Experimental Animal Model of Chronic Inflammation (original) (raw)
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Effect of exogenous melatonin on acute and chronic inflammatory process in rats
Acta farmacéutica bonaerense, 2002
Melatonin influence (4 mg/kg) was investigated on acute inflammation using rat paw edema and on chronic inflammation through granuloma test and adjuvant arthritis. Melatonin inhibited the edema produced by carrageenan in acute model. However, failed to inhibit the proliferative phase in the granuloma test and the acute and chronic phase in the adjuvant arthritis. These results suggest melatonin shows different activity on the tested inflammatory models at the same doses. RESUMEN. "Efecto de melatonina exógena en procesos inflamatorios agudos y crónicos en ratas". Se investigó la influencia de melatonina (4 mg/kg) en la inflamación aguda usando el modelo de edema de pata en rata y en la inflamación crónica mediante la prueba del granuloma y artritis inducida por adyuvante. Melatonina inhibió el edema producido por carragenina en el modelo agudo, pero no presentó acción inhibitoria en la fase proliferativa de la prueba del granuloma y en la fase aguda y crónica de la artritis inducida por adyuvante. Estos resultados sugieren que melatonina, a la misma dosis, muestra diferentes comportamientos en los modelos inflamatorios ensayados.
Melatonin ameliorates low-grade inflammation 2013
The aim of this study was to investigate the effects of melatonin on low-grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n = 30) and lean littermates (ZL) (n = 30) were used. At 6 wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10 mg/kg/day) for 6 wk. Vehicle and melatonin were added to the drinking water. Pro-inflammatory state was evaluated by plasma levels of interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and C-reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe 2+ /H 2 O 2 inducement. ZDF rats exhibited higher levels of IL-6 (112.4 ± 1.5 pg/mL), TNF-a (11.0 ± 0.1 pg/mL) and CRP (828 ± 16.0 µg/mL) compared with lean rats (IL-6, 89.9 ± 1.0, P < 0.01; TNF-a, 9.7 ± 0.4, P < 0.01; CRP, 508 ± 21.5, P < 0.001). Melatonin lowered IL-6 (10%, P < 0.05), TNF-a (10%, P < 0.05), and CRP (21%, P < 0.01). Basal and Fe 2+ /H 2 O 2 -induced LPO, expressed as malondialdehyde equivalents (µmol/L), were higher in ZDF rats (basal, 3.2 ± 0.1 versus 2.5 ± 0.1 in ZL, P < 0.01; Fe 2+ /H 2 O 2 -induced, 8.7 ± 0.2 versus 5.5 ± 0.3 in ZL; P < 0.001). Melatonin improved basal LPO (15%, P < 0.05) in ZDF rats, and Fe 2+ /H 2 O 2 -induced LPO in both ZL (15.2%, P < 0.01) and ZDF rats (39%, P < 0.001). These results demonstrated that oral melatonin administration ameliorates the pro-inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease.
Journal of pineal research, 2012
Abstract: Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin’s anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2-related factor 2, and others. Melatonin’s effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole’s anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin’s anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues.
Melatonin: A pleiotropic molecule regulating inflammation
Biochemical Pharmacology, 2010
Melatonin is a neurohormone produced by the pineal gland that regulates sleep and circadian functions. Melatonin also regulates inflammatory and immune processes acting as both an activator and inhibitor of these responses. Melatonin demonstrates endocrine, but also paracrine and autocrine effects in the leukocyte compartment: on one side, leukocytes respond to melatonin in a circadian fashion; on the other side, leukocytes are able to synthesize melatonin by themselves. With its endocrine and paracrine effects, melatonin differentially modulates pro-inflammatory enzymes, controls production of inflammatory mediators such as cytokines and leukotrienes and regulates the lifespan of leukocytes by interfering with apoptotic processes. Moreover, its potent anti-oxidant ability allows scavenging of oxidative stress in the inflamed tissues. The interesting timing of pro-and anti-inflammatory effects, such as those affecting lipoxygenase activity, suggests that melatonin might promote early phases of inflammation on one hand and contribute to its attenuation on the other hand, in order to avoid complications of chronic inflammation. This review aims at giving a comprehensive overview of the various inflammatory pathways regulated by this pleiotropic hormone.
Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin's anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2-related factor 2, and others. Melatonin's effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole's anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin's anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues
2005
Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE 2 and nitric oxide. Another endogenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential antiinflammatory agents without the classical side effects due to COX-1 inhibition. D
Efecto de melatonina exógena en procesos inflamatorios agudos y crónicos en ratas
Acta Farmacéutica Bonaerense, 2002
Melatonin influence (4 mg/kg) was investigated on acute inflammation using rat paw edema and on chronic inflammation through granuloma test and adjuvant arthritis. Melatonin inhibited the edema produced by carrageenan in acute model. However, failed to inhibit the proliferative phase in the granuloma test and the acute and chronic phase in the adjuvant arthritis. These results suggest melatonin shows different activity on the tested inflammatory models at the same doses. RESUMEN. "Efecto de melatonina exógena en procesos inflamatorios agudos y crónicos en ratas". Se investigó la influencia de melatonina (4 mg/kg) en la inflamación aguda usando el modelo de edema de pata en rata y en la inflamación crónica mediante la prueba del granuloma y artritis inducida por adyuvante. Melatonina inhibió el edema producido por carragenina en el modelo agudo, pero no presentó acción inhibitoria en la fase proliferativa de la prueba del granuloma y en la fase aguda y crónica de la artritis inducida por adyuvante. Estos resultados sugieren que melatonina, a la misma dosis, muestra diferentes comportamientos en los modelos inflamatorios ensayados.
Melatonin administration reduces inflammatory pain in rats
Journal of Pain Research, 2012
In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.
Different Effects of Melatonin on Experimental Granulomatous Inflammation
Inflammation, 2004
Several experiments have detected that melatonin exerts a marked influence on the inflammatory process. In the present study we evaluated the effect of exogenous melatonin on the experimental granulomatous tissues in rat. Our data show that subcutaneous administration of different doses of melatonin given daily during 6 days at 9:00 h do not have significant action on the granuloma weight. On the other hand melatonin (4 mg/kg) administered at 17:00 h showed a remarkable action pro-inflammatory. However, this effect was abolished when the animals received previously higher doses of melatonin (40 mg/kg) at 9:00 h.