Topical H2 receptor antagonist (cimetidine) application prevents Porphyromonas gingivalis induced periodontitis in rabbits
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Abstract
The periodontal diseases are infectious diseases associated with specific pathogenic bacteria. As our understanding of the pathogenesis of the periodontal diseases grows, it is becoming clear that most of the tissue damage is caused by the host response to infection, not by the infectious agents directly. Histamine, released from mast cells and basophils during inflammatory reactions, can affect the immune response through H1 and H2 receptors. There is accumulating evidence that histamine acts as a modulator of inflammation and immunological events such as inhibition of T-lymphocyte and natural killer cell-mediated cytotoxicity. In addition, histamine inhibits chemotaxis of neutrophils, superoxide production, but increases levels of cAMP and downregulates both TH1 and TH2 cytokines. The histamine H2 receptor is a member of the G protein coupled receptor family involved in the regulation of multiple physiological events extending from gastric secretion to tissue inflammation. H2 receptor antagonists (such as cimetidine, ranitidine, and metiamide) reverse the effects of histamine. These specific inhibitors are also widely recognized to modulate T-cell function through inhibiting T-suppressor cell function and enhancing natural killer cell function. Cimetidine is a specific competitive histamine H2 receptor antagonist, which inhibits the histamine stimulated release of gastric acid and therefore used widely for the treatment of peptic ulcer. It is a powerful H2 receptor antagonist which, eliminates the histamine’s inhibitory effects on chemotaxis, phagocytosis, superoxide anion production and the production of TNF[alpha] and IL-12 by macrophages via histamine H2 receptor indicates the interactions between histamine and the host defense system.
The purpose of this study was to quantitatively analyze the histopathologic changes associated with experimental periodontitis in rabbits in response to topically applied H2 receptor antagonist (cimetidine). Experimental periodontitis was induced in 1 7 New Zealand white rabbits with silk sutures tied around mandibular second premolars bilaterally, followed by the topical application of 1O[8]-10[9] CFU of Porphyromonas gingivalis (P. gingivalis). The experimental periodontitis group (n=2) received ligature and P. gjngivalis while the vehicle group (n=3) received liposome preparation without cimetidine in addition to ligature and P. gingivalis. Effect of different doses of cimetidine was tested on 12 rabbits with 4 animals in 3 groups. These animals received cimetidine at doses of 0.1, 1.0, or 10.0 [mu]g/mI in addition to the ligature placement and P. gingivalis administration. The topical application of the pharmacologic preparations and bacteria was done three times per week for 6 weeks. Rabbits were euthanized after 6 weeks and mandibular block sections were obtained. Blocks were decalcified and embedded with paraffin. A total of three hundred forty 5[mu]m sections were stained with Hematoxylin-Eosin and one hundred seventy 5[mu]m sections were stained with tartrate-resistant acid phosphatase (TRAP). Histologic evaluation of samples, characterization of cellular inflammatory infiltrate and quantitative histomorphometric measurements were made.
The results confirmed that periodontal tissue destruction could be induced by the topical application of ligature and P. gingivalis. These pathological tissue changes were completely prevented with simultaneous topical administration of cimetidine. The histomorphometric analysis of the histologic sections suggested that cimetidine could act as a preventive measure against the development of periodontal disease. Increased multinucleated osteoclastic cells with resorptive lacunae and inflammatory infiltrate dominated the pathological sections of the experimental periodontitis and liposome groups. The ligatured sites of the control and vehicle groups showed significant differences in the linear distances, ratio measurements and area calculations of the alveolar bone at the three chosen levels-the tip, middle and the base of the crest (p[0.05) as compared to the other three groups, which indicated the destruction of the alveolar crest due to the disease activity in the control and vehicle groups. The findings of this study provide histologic evidence that topically active cimetidine were potent inhibitors of P. gingivalis-elicited leukocyte migration toward a site of infection, therefore arresting and/or preventing tissue destruction and influencing cell populations present in the inflammatory cell infiltrate. In conclusion, topical application of cimetidine was effective in preventing bone loss, inflammatory cell infiltration and connective tissue destruction in the rabbit periodontitis model which, may be a potential candidate for pharmacologic host modulator agents to prevent periodontitis.
Description
Thesis (M.S.D.)--Boston University, Henry M. Goldman School of Dental Medicine, 2004 (Periodontology and Oral Biology).
Includes bibliographical references (leaves 63-76).
Includes bibliographical references (leaves 63-76).
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This work is being made available in OpenBU by permission of its author, and is available for research purposes only. All rights are reserved to the author.