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      Effect of topical application of melatonin on serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with type 1 or type 2 diabetes and periodontal disease

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          The present clinical trial study was designed to assess the effect of topical application of melatonin on serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP) in patients with diabetes and periodontal disease in comparison with healthy controls.

          Material and Methods

          Serum levels of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay and CRP by nephelometry by using the proper commercial kits in 30 patients with diabetes and periodontal disease, and also in a control group of 30 healthy subjects. Periodontograms were performed using the Florida Probe®. Patients with diabetes were treated with a topical application of melatonin (1% orabase cream formula) once daily for 20 days. Healthy subjects were treated with a placebo orabase cream.


          Patients with diabetes and periodontal disease had significantly higher mean levels of serum TNF-α, IL-6 and CRP than healthy subjects ( P < 0.001). Following topical melatonin application, there was a statistically significant decrease in the gingival index and pocket depth ( P < 0.001) as well as a significant decrease in IL-6 and CRP serum levels ( P < 0.001). Local melatonin application in patients with diabetes and periodontal disease resulted in a significant decrease in CRP and IL-6 serum levels as well as an improvement in the gingival index and pocket depth. Patients with periodontal disease had significantly higher serum CRP, IL-6 and TNF-α values by comparison with healthy subjects.


          We conclude that melatonin can modulate the inflammatory action of these molecules in periodontal patients.

          Key words:Melatonin, periodontal disease, diabetes mellitus, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, inflammatory markers.

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          Most cited references 27

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          A systematic review and meta-analyses on C-reactive protein in relation to periodontitis.

          Elevated plasma C-reactive protein (CRP) is regarded as a risk predictor for cardiovascular diseases. This systematic review explored the robustness of observations that CRP is elevated in periodontitis. Similarly, the effect of periodontal therapy on CRP levels was investigated. Selection of publications was based on: (1) cross-sectional (case-control) studies; (2) longitudinal (treatment) studies; (3) high-sensitivity CRP measurement; (4) median and/or mean (+/-SD) values presented; and (5) subjects with no systemic disorders. Screening of the initially 448 identified studies and reference checking resulted in 18 suitable papers. The majority of the studies showed that CRP levels are higher in patients than in controls. Often, studies showed that patients had CRP levels >2.1 mg/l. A meta-analysis of 10 cross-sectional studies showed that the weighted mean difference (WMD) of CRP between patients and controls was 1.56 mg/l (p<0.00001). Evidence from available treatment studies (n=6) showed lower levels of CRP after periodontal therapy. Eligible treatment studies in a meta-analysis demonstrated a WMD of reductions of CRP after therapy of 0.50 mg/L (95% CI 0.08-0.93) (p=0.02). There is strong evidence from cross-sectional studies that plasma CRP in periodontitis is elevated compared with controls. There is modest evidence on the effect of periodontal therapy in lowering the levels of CRP.
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            Association of periodontitis with rheumatoid arthritis: a pilot study.

            Similarities exist in the epidemiology and immunopathogenesis of periodontitis and rheumatoid arthritis (RA), but the associations between their respective disease activities and severities are less well documented. We evaluated the prevalence and severity of periodontitis in United States (U.S.) veterans with RA and their relationship to RA disease activity and severity. Patients with RA from an outpatient rheumatology clinic were eligible, and patients with osteoarthritis (OA) served as controls. Dentists, masked to the rheumatologic diagnoses, performed periodontal probing and examined dental panoramic radiographs to assess the presence and severity of periodontitis. Associations of periodontitis with RA were examined using multivariate regression, whereas the association of periodontitis with disease-severity measures in RA was examined using the chi(2) test. Sixty-nine patients with RA (57 males and 12 females) and 35 patients with OA (30 males and five females) were studied. Moderate to severe periodontitis was more prevalent in patients with RA (51%) than controls (26%) (P = 0.03), an association independent of age, race, smoking, diabetes mellitus, and gender. Patients with RA who were seropositive for rheumatoid factor (RF) were more likely to have moderate to severe periodontitis (59%) than patients who were RF negative (15%) (P = 0.02). Likewise, patients with RA who were positive for the anti-cyclic citrullinated peptide (CCP) antibodies were more likely to have moderate to severe periodontitis (56%) than patients who were anti-CCP negative (22%) (P = 0.01). There were no associations of periodontitis status with other measures of RA disease activity or severity. In a cohort of U.S. veterans, periodontitis was more common and severe in patients with RA compared to patients with OA. Although unrelated to disease activity, the presence of periodontitis in patients with RA was associated with seropositivity for RF and the anti-CCP antibody, which was highly relevant given the associations of these autoantibodies with poor outcomes and disease pathogenesis in RA.
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              Anti-tumor necrosis factor-alpha therapy and periodontal parameters in patients with rheumatoid arthritis.

              The aim of this study was to evaluate the influence of anti-tumor necrosis factor-alpha (TNF-alpha) therapy on the clinical and immunologic parameters of the periodontium. Ten patients with rheumatoid arthritis (RA) who routinely received infusions of infliximab, 200 mg (RA+), 10 patients with RA without anti-TNF-alpha therapy (RA-), and 10 healthy controls (C) were included. Clinical parameters, including the plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (AL), and bleeding on probing (BOP), were assessed, and total gingival crevicular fluid (GCF) TNF-alpha level was determined using enzyme-linked immunosorbent assay. Analysis of variance with Scheffe modification and the Pearson correlation test were used for statistical analysis. The ages of the patients ranged from 22 to 76 years (mean, 50.73 +/- 9.1 years). The mean PI was similar among the groups. However, mean inflammatory parameters in the three groups varied significantly; GI was greater in the RA- group compared to RA+ and C groups (P = 0.0042). The RA+ group exhibited less BOP than RA- and C groups (21.1% +/- 3.0%, 45.9% +/- 6.2%, and 39.1% +/- 7.2%, respectively; P = 0.0146). The mean PD in the RA+ group was shallower than in RA- and C groups (3.22 +/- 0.13 mm, 3.85 +/- 0.22 mm, and 3.77 +/- 0.20 mm, respectively; P = 0.055). Clinical AL in the RA+ group was lower than in RA- and C groups (3.68 +/- 0.11 mm, 4.52 +/- 0.26 mm, and 4.35 +/- 0.24 mm, respectively; P = 0.0273). TNF-alpha levels in the GCF of the RA+ group were the lowest compared to RA- and C groups (0.663, 1.23, and 0.949 ng/site, respectively; P = 0.0401). A significant positive correlation was found between TNF-alpha levels in the GCF and clinical AL (r = 0.448; P = 0.0283). Patients with RA receiving anti-TNF-alpha medication had lower periodontal indices and GCF TNF-alpha levels. Thus, suppression of proinflammatory cytokines might prove beneficial in suppressing periodontal diseases.

                Author and article information

                J Clin Exp Dent
                J Clin Exp Dent
                Medicina Oral S.L.
                Journal of Clinical and Experimental Dentistry
                Medicina Oral S.L.
                1 December 2015
                December 2015
                : 7
                : 5
                : e628-e633
                [1 ]Department of Special Care in Dentistry, School of Dentistry, University of Granada, Granada, Spain
                [2 ]Department of Surgery, School of Dentistry, Faculty of Medicine, University of Salamanca, Salamanca, Spain
                [3 ]Department of Odontology, Faculty of Health Sciences, University of Alfonso X, Villanueva de la Cañada, Madrid, Spain
                [4 ]Pinos Puente Healthcare Centre, Granada-Metropolitan Health District. Granada, Spain
                Author notes
                Facultad de Medicina Departamento de Cirugía Clínica Odontológica, Universidad de Salamanca C/Alfonso X El Sabio S/N. 37007 Salamanca, Spain , E-mail: anlopezvalverde@ 123456gmail.com

                Conflict of interest statement:The authors declare no conflict of interest.

                Copyright: © 2015 Medicina Oral S.L.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



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