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      Effect of Cimetidine on Nitro-Oxidative Stress in a Rat Model of Periodontitis

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          Abstract

          Background and aims

          Periodontitis is a chronic inflammation that involves nitro-oxidative stress with damaging periodontal structural effects. We aimed to evaluate the consequences of low-dose cimetidine on nitro-oxidative stress in periodontitis.

          Methods

          A rat model of ligature-induced periodontitis was used. After two weeks, the periodontitis groups were treated with cimetidine, aminoguanidine, N-nitro-L-arginine methyl ester and trolox for one week. On day 21, blood was drawn and the serum analyzed for measurement of total nitrites and nitrates, total oxidative status, total antioxidant response, and oxidative stress index.

          Results

          Cimetidine had an inhibitory effect on the synthesis of nitric oxide (p=0.001), total oxidative status (p=0.01) and oxidative stress index (p=0.01). Total antioxidant reactivity was increased by cimetidine (p=0.01). The effects of cimetidine were almost like those of aminoguanidine, NG-nitro-L-arginine methyl ester, and trolox.

          Conclusions

          Low-dose cimetidine can be used as adjunctive host modulatory therapy in chronic periodontitis because it reduces nitro-oxidative stress.

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          Most cited references26

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          The chemical biology of nitric oxide: implications in cellular signaling.

          Nitric oxide (NO) has earned the reputation of being a signaling mediator with many diverse and often opposing biological activities. The diversity in response to this simple diatomic molecule comes from the enormous variety of chemical reactions and biological properties associated with it. In the past few years, the importance of steady-state NO concentrations has emerged as a key determinant of its biological function. Precise cellular responses are differentially regulated by specific NO concentration. We propose five basic distinct concentration levels of NO activity: cGMP-mediated processes ([NO] 400 nM), and nitrosative stress (1 microM). In general, lower NO concentrations promote cell survival and proliferation, whereas higher levels favor cell cycle arrest, apoptosis, and senescence. Free radical interactions will also influence NO signaling. One of the consequences of reactive oxygen species generation is to reduce NO concentrations. This antagonizes the signaling of nitric oxide and in some cases results in converting a cell-cycle arrest profile to a cell survival profile. The resulting reactive nitrogen species that are generated from these reactions can also have biological effects and increase oxidative and nitrosative stress responses. A number of factors determine the formation of NO and its concentration, such as diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. These are the chemical and biochemical parameters that shape cellular responses to NO. Herein we discuss signal transduction and the chemical biology of NO in terms of the direct and indirect reactions.
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            Cytokines that promote periodontal tissue destruction.

            Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment and may directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease.
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              Immune response: the key to bone resorption in periodontal disease.

              Periodontal disease infection with oral biofilm microorganisms initiates host immune response and signs of periodontitis, including bone resorption. This review delineates some mechanisms underlying the host immune response in periodontal infection and alveolar bone resorption. Activated T lymphocytes have been historically implicated in experimental periodontal bone resorption. An experimental rat adoptive transfer/gingival challenge periodontal disease model has been demonstrated to require antigen-specific T lymphocytes and gingival instillation of antigen and LPS for bone resorption. Interference with costimulatory interactions between T cells and antigen-presenting cells abrogated bone resorption, further emphasizing the significance of immune response in periodontal disease. Receptor activator of nuclear factor kappaB ligand (RANKL), a critical osteoclast differentiation factor, is expressed on T lymphocytes in human periodontal disease as determined by immunohistochemical and confocal microscopic analyses. Interference with RANKL by systemic administration of osteoprotegerin (OPG), the decoy receptor for (and inhibitor of) RANKL, resulted in abrogation of periodontal bone resorption in the rat model. This finding indicated that T cell-mediated bone resorption is RANKL-dependent. In additional experiments, treatment of T cell-transferred rats with kaliotoxin (a scorpion venom potassium channel inhibitor) resulted in decreases in T-cell RANKL expression, diminished induction of RANKL-dependent osteoclastogenesis, and abrogation of bone resorption, implicating an important role of immune response/RANKL expression in osteoclastogenesis/bone resorption. In other experiments, adoptive transfer of antigen-specific, RANKL-expressing B cells, and infection with the antigen-bearing Actinobaccillus actinomycetemcomitans gave rise to periodontal bone resorption, indicating that B cells also have the capacity to mediate bone resorption, probably via RANKL expression. In humans, prominent T lymphocytes have been identified in periodontal disease, and diseased tissues showed elevated RANKL mRNA expression, as well as decreased OPG mRNA expression. Mononuclear cells from periodontal lesions involving T cells and B cells of patients induced osteoclastogenesis in vitro. In summary, a biofilm interface initiates immune cell infiltration, stimulating osteoclastogenesis/bone resorption in periodontal disease. This resorption can be ameliorated by inhibition of RANKL activity or by diminishing immune cell stimulation. These two procedures, if localized, have the potential to lead to the prevention or therapeutic management of periodontal disease and therefore require further study.
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                Author and article information

                Journal
                Clujul Med
                Clujul Med
                CM
                Clujul Medical
                Iuliu Hatieganu University of Medicine and Pharmacy
                1222-2119
                2066-8872
                2014
                05 August 2014
                : 87
                : 3
                : 177-181
                Affiliations
                [1 ]Department of Odontology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
                [2 ]Department of Pathophysiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
                [3 ]Department of Periodontology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
                [4 ]Department of Propedeutics and Dental Materials, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
                Author notes
                Address for correspondence: parvualinaelena@ 123456yahoo.com
                Article
                cm8703p177
                10.15386/cjmed-273
                4508593
                26528020
                7d9d2075-012b-4b1a-80f5-82f955c919c0
                Copyright @ 2014

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

                History
                : 08 April 2014
                : 06 July 2014
                : 23 June 2014
                Categories
                Original Research
                Dental Medicine

                periodontitis,nitric oxide,oxidative stress,cimetidine
                periodontitis, nitric oxide, oxidative stress, cimetidine

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