Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Melatonin reduces oxidative stress in surgical neonates. The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial Analgesic and antihyperalgesic effects of melatonin in a human inflammatory pain model: a randomized, double-blind, placebo-controlled, three-arm crossover study A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Utility of melatonin to treat surgical stress after major vascular surgery--a safety study. Cognitive Behavioral Therapy and Tai Chi Reverse Cellular and Genomic Markers of Inflammation in Late Life Insomnia: A Randomized Controlled Trial Analgesic and sedative effects of melatonin in temporomandibular disorders: a double-blind, randomized, parallel-group, placebo-controlled study. Effect of combined treatment with melatonin and methylprednisolone on neurological recovery after experimental spinal cord injury Effect of vitamin D supplementation on inflammation: protocol for a systematic review Effects of Antioxidant Supplements Intervention on the Level of Plasma Inflammatory Molecules and Disease Severity of Rheumatoid Arthritis Patients The effects of melatonin administration on disease severity and sleep quality in children with atopic dermatitis: A randomized, double‐blinded, placebo‐controlled trial Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin Short- but Not Long-Term Melatonin Administration Reduces Central Levels of Brain-Derived Neurotrophic Factor in Rats with Inflammatory Pain Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients. Pharmacokinetics of orally administered melatonin in critically ill patients. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment.
Multiple sclerosis ( MS ) is a chronic inflammatory disease , which leads to focal plaques of demyelination and tissue injury in the central nervous system ( CNS ) . Neuroinflammation and oxidative stress are involved in the pathogenesis of MS , promoting tissue damage and demielinization . Current research findings suggest that melatonin has antioxidant and neuroprotective effects . The aim of this study was to evaluate the efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing-remitting multiple sclerosis ( RRMS ) . 36 patients diagnose with RRMS treated with Interferon β-1b ( IFNβ-1b ) were enrolled in a double bind , r and omized , placebo controlled trial . The experimental group received orally 25 mg/d of melatonin for 6 months . After melatonin administration , we observed a significant decrease in serum concentration of pro-inflammatory cytokines and oxidative stress markers ; 18 % for TNF-α ( p < 0.05 ) , 34.8 % for IL-1β ( p < 0.05 ) , 34.7 % for IL-6 ( p < 0.05 ) , 39.9 % for lipoperoxides ( LPO ) ( p < 0.05 ) and 24 % for nitric oxide catabolites ( NOC ) levels ( p < 0.05 ) , compared with placebo group . No significant difference in clinical efficacy outcomes were found between groups . Melatonin treatment was well tolerated and we did not observe significant differences in rates of side effects between the two groups . We concluded that melatonin administration during 6 months period is effective in reducing levels of serum pro-inflammatory cytokines and oxidative stress markers in patients with RRMS . These data support future studies evaluating the safety and effectiveness of melatonin supplementation in RRMS patients BACKGROUND / PURPOSE Cytokines are inflammatory mediators found in the circulation after surgery . Newborns have less protection against oxidation and are very susceptible to free radical oxidative damage . Melatonin has been reported recently to reduce oxidative stress in neonates with sepsis , asphyxia , and respiratory distress . The aim of this study has been to determine if melatonin would lower interleukin (IL)-6 , IL-8 , tumor necrosis factor alpha ( TNF-alpha ) and nitrite/nitrate ( NOx ) levels and modify serum inflammation parameters , improving the clinical course of surgical neonates . METHODS Ten newborns ( group 1 ) , 5 with surgical malformations and respiratory distress ( group 1a ) and 5 with isolated abdominal surgical malformations ( group 1b ) received a total of 10 doses of melatonin ( 10 mg/kg ) at defined times interval for 72 hours . The treatment was started within 3 hours after the end of surgery . Ten surgical neonates ( group 2 ) , did not receive melatonin .  Twenty healthy neonates ( group 3 ) served as control . Blood sample s were collected at the end of operation ; before treatment with the antioxidant ; and 24 hours 72 hours , and 7 days after start of treatment with melatonin or placebo , respectively . RESULTS Postoperative value of cytokines and NOx levels of groups 1 and 2 were significantly higher than group 3 . Compared with group 1b , group 2 displayed significantly higher cytokines and NOx levels at 24 hours , 72 hours , and at 7 days . In group 1a the immediate postoperative values of cytokines were significantly higher than group 1b and group 2 , but a significant improvement was observed after administration of melatonin with significantly lower levels of IL-6 and IL-8 with respect to group 2 . An improvement of clinical outcome was observed by progressive reduction of clinical parameters of inflammation . CONCLUSIONS Melatonin reduces cytokines and NOx levels showing potent antioxidant properties with improvement in clinical outcome . Further studies are warranted to define , on larger numbers , the role of melatonin in surgical patients Background Diabetes mellitus ( DM ) and periodontitis are two common chronic diseases with bidirectional relationship . Oxidative stress plays a key role in the pathogenesis of these two diseases . The aim of this study was to investigate the effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status , serum melatonin and inflammatory markers in type 2 DM patients with chronic periodontitis ( CP ) . Material s and methods In this double-blind clinical trial study , 50 type 2 DM patients with CP were r and omly allocated to the intervention and control groups . The intervention and control groups received either 6 mg melatonin or placebo ( 2 tablets ) once a day . Serum levels of melatonin , tumor necrosis factor-alpha ( TNF-α ) , interleukin-6 ( IL-6 ) , hs-C-reactive protein ( hs-CRP ) , clinical attachment loss ( CAL ) , pocket depth ( PD ) , bleeding on probing ( BOP ) and plaque index were evaluated in all subjects pre- and post-intervention . Results Melatonin supplementation significantly increased the mean serum levels of melatonin after intervention . The mean changes of melatonin were significantly higher in intervention group compared with control group . IL-6 and hs-CRP levels were significantly ( p = 0.008 and p = 0.017 , respectively ) reduced in the intervention group . The mean changes of IL-6 were significantly lower in the intervention group compared with the control group ( p = 0.04 ) . In the intervention group , PD and CAL were significantly decreased after intervention ( p < 0.001 ) . There were significant differences in the mean change of PD and CAL between the intervention and control groups after intervention ( p < 0.001 ) . Conclusions Melatonin supplementation in adjunct with non-surgical periodontal therapy might improve inflammatory and periodontal status in T2DM with CP Abstract Antinociceptive effects of melatonin have been documented in a wide range of experimental animal models . The aim of this study was to investigate the analgesic , antihyperalgesic , and anti-inflammatory properties of melatonin using a vali date d burn injury ( BI ) model in healthy male volunteers . The design was a r and omized , double-blind , placebo-controlled , three-arm crossover study . Each volunteer participated in 3 identical study sessions with intravenous administration of placebo , melatonin 10 mg , or melatonin 100 mg . Sixty minutes after bolus injection of study medication , a BI was induced by a computerized contact thermode ( 47.0 ° C , 420 seconds , 5.0 × 2.5 cm2 ) . Pain ratings during the BI and quantitative sensory testing at baseline and at 1 , 2 , 4 , and 6 hours after the BI were performed . Quantitative sensory testing included assessment s of secondary hyperalgesia areas , mechanical and thermal thresholds in the BI area , and pressure algometry . Furthermore , markers of inflammation , skin-reflectance spectrophotometry , and high-resolution ultrasonography were applied to measure skin erythema and dermal thickness in the BI area . Pain during the BI and secondary hyperalgesia areas were defined as primary outcomes . Twenty-nine volunteers were r and omized and completed the study . While the BI induced large secondary hyperalgesia areas and significantly increased the markers of inflammation , no significant effects of melatonin were observed with respect to primary or secondary outcomes , compared with placebo . The administration of melatonin was not associated with any adverse effects . Melatonin did not demonstrate any analgesic , antihyperalgesic , or anti-inflammatory properties in the BI model Obesity , the global epidemic health problem , results in chronic disorders . Melatonin supplementation may prevent the adverse health consequences of obesity . The aim of this study was to assess the effects of melatonin supplementation on inflammatory and oxidative stress parameters in obese women . In r and omized , double-blind , placebo-controlled trial , 44 obese women were r and omly assigned to melatonin ( n=22 ) and placebo ( n=22 ) groups . Subjects were supplemented with a daily dose of 6 mg melatonin or placebo with low calorie diet for 40 days . Serum TNF-α , IL-6 , hsCRP , TAC , and MDA levels were assessed before and after intervention . In the melatonin group , mean serum TNF-α , IL-6 , hsCRP , and MDA levels decreased significantly ( p<0.05 ) from 3.52±0.72 pg/ml , 27.12±6.32 pg/ml , 2.54±0.49 mg/l , and 3.81±0.29 nmol/l to 1.73±0.07 , 16.34±6.32 , 1.67±0.27 , and 2.79±0.29 , respectively . Whilst in the placebo group the decrease in values were not statistically significant . Mean TAC level increased slightly ( from 1.11±0.30 to 1.14±0.45 mmol/l ) in the melatonin group whereas it decreased slightly ( from 1.13±0.15 to 1.08±0.21 nmol/l ) in the placebo group . Significant differences were observed only for TNF-α ( p=0.02 ) and IL-6 ( p=0.03 ) between the 2 study groups . Considering the improvements in inflammatory and oxidative stress factors in obese women , it seems that melatonin supplementation may provide beneficial effects in obesity treatment by ameliorating some of its complications . However , further studies are needed to make concise conclusions Surgery for abdominal aortic aneurysm is associated with elevated oxidative stress . As an antioxidant in animal and human studies , melatonin has the potential of ameliorating some of this oxidative stress , but melatonin has never been administered to adults during surgery for the purpose of reducing oxidative damage . The aim of this pilot study was to evaluate the safety of various doses of melatonin administered during or after surgery and to monitor the changes in biomarkers of oxidative stress and inflammation during the pre- , intra- , and postoperative period . Six patients undergoing aortic surgery received 10 ( n = 2 ) , 30 ( n = 2 ) or 60 ( n = 2 ) mg melatonin intravenously in the intraoperative phase and 10 mg orally for three nights after surgery . Patients were monitored for hemodynamic parameters during and after surgery . Any unexpected events during the hospitalization were registered . Blood sample s were collected preoperatively and at 5 min , 6 hr and 24 hr after clamp removal or after re-circulation of the first leg and the sample s were analyzed for malondialdehyde ( MDA ) , ascorbic acid ( AA ) , dehydroascorbic acid ( DHA ) , and interleukin-6 ( IL-6 ) . Troponin I ( TpI ) and C-reactive protein ( CRP ) were also measured for 4 days after surgery . Melatonin administration did not change hemodynamic parameters ( mean arterial pressure or pulse rate ) during surgery ( P = 0.499 and 0.149 , respectively ) , but oxidative stress parameters ( MDA and AA ) decreased significantly ( P = 0.014 and 0.001 , respectively ) . There was a significant increase in the inflammatory parameters ( IL-6 and CRP ) ( P = 0.001 and 0.001 , respectively ) and an increase in TpI ( P = 0.009 ) as a consequence of surgery . These were not influenced by melatonin treatment . Treatment of patients undergoing major aortic surgery with melatonin intravenously up to 60 mg in the intraoperative phase was safe and without complications . Melatonin may decrease oxidative damage result ing from surgery , but r and omized clinical trials are required before definitive conclusions can be drawn regarding the clinical benefit of melatonin in surgical situations Background Sleep disturbance is associated with activation of systemic and cellular inflammation , as well as pro-inflammatory transcriptional profiles in circulating leukocytes . Whether treatments that target insomnia-related complaints might reverse these markers of inflammation in older adults with insomnia is not known . Methods In this r and omized trial , 123 older adults with insomnia were r and omly assigned to cognitive behavioral therapy for insomnia ( CBT-I ) , tai chi chih ( TCC ) , or sleep seminar education active control condition ( SS ) for two hour sessions weekly over 4 months with follow-up at 7- and 16-months . We measured C-reactive protein ( CRP ) at baseline , month 4 and 16 , Toll-like receptor-4 (TLR-4)-activated monocyte production of proinflammatory cytokines at baseline , month 2 , 4 , 7 , and 16 , and genome-wide transcriptional profiling at baseline and month 4 . Results As compared to SS active control , CBT-I  reduced levels of CRP ( month 4 , 16 , P’s<0.05 ) , monocyte production of proinflammatory cytokines ( month 2 only , P<0.05 ) , and pro-inflammatory gene expression ( month 4 , P<0.01 ) . TCC marginally reduced CRP ( month 4 , P=0.06 ) , and significantly reduced monocyte production of proinflammatory cytokines ( month 2 , 4 , 7 , 16 , all P’s<0.05 ) and proinflammatory gene expression ( month 4 , P<0.001 ) . In CBT and TCC , TELIS promoter-based bioinformatics analyses indicated reduced activity of nuclear factor (NF)-κB and AP1 . Conclusions Among older adults with insomnia , CBT-I reduced systemic inflammation , TCC reduced cellular inflammatory responses , and both treatments reduced expression of genes encoding proinflammatory mediators . The findings provide an evidence -based molecular framework to underst and the potential salutary effects of insomnia treatment on inflammation , with implication s for inflammatory disease risk CONTEXT The association between myofascial temporom and ibular disorder ( TMD ) and nonrestorative sleep supports the investigation of therapies that can modulate the sleep/wake cycle . In this context , melatonin becomes an attractive treatment option for myofascial TMD pain . OBJECTIVES To investigate the effects of melatonin on pain ( primary aim ) and sleep ( secondary aim ) as compared with placebo in a double-blind , r and omized , parallel-group trial . METHODS Thirty-two females , aged 20 - 40 years , with myofascial TMD pain were r and omized into placebo or melatonin ( 5 mg ) treatment groups for a period of four weeks . RESULTS There was a significant interaction ( time vs. group ) for the main outcomes of pain scores as indexed by the visual analogue scale and pressure pain threshold ( analysis of variance ; P<0.05 for these analyses ) . Post hoc analysis showed that the treatment reduced pain scores by -44 % ( 95 % CI -57 % , -26 % ) compared with placebo , and it also increased the pressure pain threshold by 39 % ( 95 % CI 14 % , 54 % ) . The use of analgesic doses significantly decreased with time ( P<0.01 ) . The daily analgesic doses decreased by -66 % ( 95 % CI -94 % , -41 % ) when comparing the two groups . Additionally , melatonin improved sleep quality , but its effect on pain was independent of the effect on sleep quality . CONCLUSION This study provides additional evidence supporting the analgesic effects of  melatonin  on pain scores and analgesic consumption in patients with mild-to-moderate chronic myofascial TMD pain . Furthermore , melatonin improves sleep quality but its effect on pain appears to be independent of changes in sleep quality Spinal cord injury ( SCI ) results in the loss of function below the lesion . Secondary injury following the primary impact includes a number of biochemical and cellular alterations leading to tissue necrosis and cell death . Methylprednisolone ( MP ) , by reducing edema and protecting the cell membrane against peroxidation , is the only pharmacological agent with a proven clinical ly beneficial effect on SCI . Melatonin , known as a free radical scavenger , has been shown to have an effect on lipid peroxidation following experimental SCI . The purpose of this study was to examine the effect of MP and melatonin on neurological , ultrastructural , and electrophysiological recovery .  Female albino rats weighing 200–250 g were r and omized into five groups of 18 rats each and six rats for the control group . Weight-drop trauma was performed for each group and a 30-mg/kg single dose of MP for rats in group 1 , a 10-mg/kg single dose of melatonin for rats in group 2 , and MP and melatonin in the same doses for rats in group 3 were administered immediately after trauma . The rats in group 4 were the vehicle group ( treated with ethanol ) and group 5 was the trauma group . The motor and somatosensory evoked potentials were recorded at the 4th hour , the 24th hour , and on the 10th day of the study for six rats in each group . Posttraumatic neurological recovery was recorded for 10 days using “ motor function score ” and inclined plane test . After electrophysiological study the rats were terminated for an analysis of lipid peroxidation level of the injured site of the spinal cord . Electron microscopic studies were performed to determine the effects of melatonin , MP , and the combined treatment with MP and melatonin on axons , neurons , myelin , nucleus , and intracytoplasmic edema . The groups treated with MP , melatonin , and a combination of both had significantly enhanced electrophysiological , biochemical , and neurological recovery and also showed better ultrastructural findings than the trauma and vehicle groups . Although combined treatment was significantly more effective on lipid peroxidation than melatonin or MP treatments alone , at the 10th day , neurobehavioral , electrophysiological , and ultrastructural recovery were at the same level . In conclusion , MP , melatonin , and MP and melatonin combined treatment modalities improved functional recovery at the same level . Future studies involving different doses of melatonin and different dose combinations with MP could promise better results since each drug has a different antioxidative mechanism of action Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 Objective : Excess generation of reactive oxygen species in damaged joints accelerates inflammatory responses in RA ( rheumatoid arthritis ) patients . The complementary effects of dietary antioxidant supplementation on the blood level of inflammatory mediators and the severity of the disease in RA patients were evaluated . Study Design and Setting s : The study was conducted as a r and omized , placebo-controlled , double-blind , three-treatment cross-over design trial . The participants visited the hospital as out patients . Subjects : Twenty patients meeting the 1987 criteria for the classification of rheumatoid arthritis completed the study . Interventions : The subjects were r and omized in three groups to receive one of following supplementation ; quercetin+vitamin C ( 166mg+133mg/capsule ) , α-lipoic acid ( 300mg/capsule ) or placebo for 4 weeks ( 3 capsules/day ) . Each treatment period consisted of 4 weeks with 2 weeks of wash-out period before the subject starts next supplementation . Outcome Parameters : Serum levels of tumor necrosis factor-α(TNF-α ) , interleukin-1β(IL-1β ) , interleukin -6(IL-6 ) , and C-reactive protein ( CRP ) were measured . The severity of disease was evaluated using Korean Health Assessment Question naire(KHAQ ) and Visual Analogue Scale(VAS ) . Nutrient intake was measured at baseline and at the end of each intervention period . Results : The mean energy and nutrient intakes remained constant during study period . No significant differences were found in the serum concentrations of pro-inflammatory cytokines and CRP between treatments . The scores of disease severity measurements were not significantly different between treatments , although quercetin supplementation had a tendency to reduce VAS . Conclusions : Dietary supplementation of antioxidants at 900 mg/day for 4 weeks did not change the blood biomarkers of inflammation and disease severity of RA patients under conventional medical treatments . Further considerations for dose-response relationships , duration of supplementation , and susceptible biomarkers are required BACKGROUND The aim of this clinical trial was to determine the effects of melatonin administration on disease severity and sleep quality in children diagnosed with atopic dermatitis ( AD ) . METHODS This r and omized , double-blinded , placebo-controlled trial was conducted by recruiting 70 patients , aged 6 - 12 years , who had been diagnosed with AD . Study participants were r and omly allocated into two intervention groups to receive either 6 mg/d melatonin supplements or placebo ( n = 35 each group ) for 6 weeks . Severity of disease was assessed using the scoring atopic dermatitis ( SCORAD ) and objective SCORAD indices . Sleep quality was evaluated by completing the Children 's Sleep Habits Question naire ( CSHQ ) . RESULTS Following 6 weeks of intervention , melatonin supplementation significantly improved SCORAD index ( β -3.55 ; 95 % CI , -6.11 , -0.98 ; P = 0.007 ) , objective SCORAD index ( β -3.23 ; 95 % CI , -5.08 , -1.38 ; P = 0.001 ) , serum total IgE levels ( β -153.94 ku/L ; 95 % CI , -260.39 , -47.49 ; P = 0.005 ) , and CSHQ scores ( β -2.55 ; 95 % CI , -4.34 , -0.75 ; P = 0.006 ) . However , melatonin had no significant impact on pruritus scores , high-sensitivity C-reactive protein ( hs-CRP ) , sleep-onset latency , total sleep time , weight , and BMI  compared with placebo . CONCLUSIONS Overall , melatonin supplementation had beneficial effects on disease severity , serum total IgE levels , and CSHQ among children diagnosed with AD Hypotension is a frequent side-effect of cancer biotherapies with cytokines .  Cytokine-induced hypotension would mainly depend on the stimulation of nitric oxide ( NO ) production , which represents the most effective endogenous vasodilator . Moreover , it has been proven that both biological activity and toxicity of cytokines are influenced by the psychoneuroendocrine system , in particular by the pineal hormone melatonin . To investigate the possible modulatory effect of melatonin on cytokine cardiovascular toxicity , we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis-factor-α(TNF)-induced hypotension in advanced cancer patients . The study included 116 patients with advanced solid tumour , for whom no effective st and ard anticancer therapy was available , who underwent  cancer biotherapy with IL-2 ( 3 × 106 IU/day s.c . every day , 6 days/week for 4 weeks ) or with TNF ( 0.75 mg/day i.v . for 5 days ) as compassionate treatment for their disease . Patients were r and omized to be treated with or without a concomitant melatonin administration ( 40 mg/day orally in the evening , starting 7 days prior to cytokine injection ) . The occurrence of hypotension was significantly less frequent in patients concomitantly treated by melatonin than in those who received the cytokine alone , during either IL-2 or TNF immunotherapy ( IL-2 : 11/45 versus 2/46,P<0.05 ; TNF : 10/23 versus 1/12,P<0.01 ) . This study shows that melatonin may prevent hypotension occurring during cancer immunotherapy with IL-2 or TNF . Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells , we suggest that melatonin may prevent cytokine-induced hypotension by inhibiting NO production , which plays an essential role in inducing hypotension during IL-2 and TNF biotherapies Objective : To evaluate the effect of short- and long-term administration of melatonin on central brain-derived neurotrophic factor ( BDNF ) levels in rats with acute and chronic inflammatory pain . Methods : The animals were allocated to one of two experiments : experiment 1 or experiment 2 . In experiment 1 , all animals were injected with complete Freund 's adjuvant ( CFA ) to induce inflammation and were r and omly allocated to receiving melatonin ( 60 mg/kg ) or vehicle . Injections were administered 1 h after CFA and once daily for 2 more days ( for a total of 3 days of melatonin administration ) . In experiment 2 , fifteen days after CFA injection , the animals were treated with melatonin ( 50 mg/kg ) or vehicle for 8 days . The animals were killed by decapitation 24 h after the last melatonin or vehicle administration , and an ELISA assay was performed to detect BDNF expression in the spinal cord , brainstem , and prefrontal cortex of the rats in both groups . Data were analyzed using Student 's t test and the results are expressed as means ± SEM . Results : In the first experiment , the BDNF levels of the melatonin group were reduced in the prefrontal cortex ( Student 's t test , p = 0.01 ) and increased in the spinal cord ( Student 's t test , p = 0.04 ) . In experiment 2 , BDNF levels were similar in both groups for all structures ( Student 's t test , p > 0.00 for all ) . A two-way ANOVA reveled a significant effect of structures ( p = 0.0001 ) but not of treatment ( p > 0.05 ) . The prefrontal cortex presented higher BDNF levels than other structures ( ANOVA/Student-Newman-Keuls test , p = 0.0001 ) . Considering the relationship between BDNF levels in all three structures , we found an effect of central nervous system structures ( p = 0.01 ) and an interaction between treatment and structures ( p = 0.04 ) . Conclusion : The high spinal cord BDNF levels and the low prefrontal cortical BDNF levels observed in rats with acute CFA-induced inflammation  following short-term melatonin administration may be related to the pain-modulating and neuroprotective effects of this protein . Long-term melatonin administration did not alter BDNF levels in chronic inflammation INTRODUCTION Inflammation is one of the main contributory factors to the etiopathogenesis of multiple sclerosis ( MS ) . Dietary interventions with Lipia citriadora ( lemon verbena ) extracts have been proved to be effective in the prevention of inflammatory diseases . OBJECTIVES The aim of this study is to evaluate the effect of lemon verbena supplementation in pro- and anti- inflammatory serum biomarkers of patients with different clinical subtypes of multiple sclerosis . METHODS The effect of lemon verbena supplementation ( 10 % w/w verbascoside ) was evaluated in a r and omized , double-blinded placebo-controlled study with 30 participants classified in relapsing-remitting ( n=10 ) , primary progressive ( n=5 ) and secondary progressive ( n=15 ) MS presentations . Serum cytokine and C reactive protein levels were assessed in intervention and control groups for each MS clinical subtype after 28 days of dietary supplementation . RESULTS Serum levels of C reactive protein and 8 cytokines/ inflammatory ( IFN-γ , IL-12 , IL-23 , IL-6 , TNF-α , TGF-β , IL-4 and IL-10 ) markers were studied . Secondary progressive MS- supplemented patients showed C reactive protein concentrations significantly lower compared to the placebo group ( Critically ill patients exhibit reduced  melatonin secretion , both in nocturnal peaks and basal daytime levels . Oral melatonin supplementation may be useful for known sedative and antioxidant properties . Its early enteral absorption and daily pharmacokinetics were determined in two cohorts of six high-risk patients in this prospect i ve trial . During their third and fourth Intensive Care Unit ( ICU ) day , they underwent two different sets of repeated blood sample s to detect serum melatonin levels through radio-immuno-assay . Cohort 1 : sample s taken at 20:00 , 20:45 , 21:30 , 24:00 , 03:00 , 06:00 , 14:00 , 20:00 to describe the daily pharmacokinetics . Cohort 2 : 20:00 , 20:05 , 20:10 , 20:20 , 20:30 , 20:45 to study the early absorption . On ICU day 3 , endogenous levels were measured , while the absorption of exogenous melatonin  was determined on ICU day 4 after administration , at 20:00 , of 3 mg melatonin . All basal levels were below the expected values . Following enteral administration , pharmacological levels were already reached in 5 min , with a serum peak after 16 min ( half-absorption time : 3 min 17 s ) . The maximum serum level observed was 11040 pg/mL and the disappearance rate indicated a half-elimination time of 1 hr 34 min . Serum melatonin levels decreased significantly after midnight ; pharmacological levels were maintained up to 10 hr following administration . No excessive sleepiness was reported in this patient group . Critically ill patients exhibited reduced melatonin secretion , as reported in the literature . Despite the critical illness , the oral bioavailability was satisfactory : serum levels after oral administration showed basically unchanged intestinal absorption , while disappearance rate was slower than reported elsewhere in healthy volunteers The objective of the present study was to assess the toxicology of melatonin ( 10 mg ) , administered for 28 days to 40 volunteers r and omly assigned to groups receiving either melatonin ( N = 30 ) or placebo  ( N = 10 ) in a double-blind fashion . The following measurements were performed : polysomnography ( PSG ) , laboratory examinations , including complete blood count , urinalysis , sodium , potassium and calcium levels , total protein levels , albumin , blood glucose , triglycerides , total cholesterol , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , and very low-density lipoprotein ( VLDL ) , urea , creatinine , uric acid , glutamic-oxalacetic transaminase ( GOT ) , glutamic-pyruvate transaminase ( GPT ) , bilirubin , alkaline phosphatase , gama-glutamic transaminase ( GGT ) , T3 , T4 , TSH , LH/FSH , cortisol , and melatonin serum concentrations . In addition , the Epworth Somnolence Scale ( ESS ) and a sleep diary ( SD ) were also applied to the volunteers 1 wk before each PSG . In addition , the volunteers were asked about possible side effects ( SE ) that appeared during the treatment . The study was carried out according to the following timetable : Visit 0 , filling out the term of consent and inclusion criteria ; Visit 1 , PSG , laboratory examinations , ESS , SD ,  melatonin serum concentrations ; Visit 2 , SD ,  melatonin serum concentrations , SE ; Visit 3 ,  melatonin serum concentrations , PSG , ESS , SE ; Visit 4 , laboratory examinations , SE , melatonin serum concentrations , SD ; and Visit 5 , PSG , ESS , SE . Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group . No other differences between the placebo and melatonin groups were obtained . In the present study we did not observe , according to the parameters analyzed , any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study
The results of the present meta- analysis support that melatonin supplementation could be effective on ameliorating of inflammatory mediators
Inflammatory processes are involved in chronic diseases .
It has been suggested that melatonin reduces inflammation by its radical scavenging properties ; however , the results of the previous studies are inconclusive .
The objective of the present meta- analysis is to determine the direction and magnitude of melatonin supplementation effect on inflammatory biomarkers .