Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

Abstract

The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects presenting with commonly prevalent comorbidities addressed here.

Structure and Mechanism of Cysteine Peptidase Gingipain K (Kgp), a Major Virulence Factor of Porphyromonas gingivalis in Periodontitis

“…It evades the host defense mechanisms through a panel of virulence factors that deregulate innate immune and inflammatory responses. In addition, bacteria and their products can enter the circulation, contributing to development and severity of systemic diseases at distal sites, such as cardiovascular diseases (6), rheumatoid arthritis (7), diabetes (8), and preterm delivery (9). Currently, specific treatment of severe periodontitis consists only of curettage of the affected area, which is time-consuming, painful, and needs frequent repetition (10), and the adjunct doxycycline hyclate (Periostat), which targets matrix metalloproteinases and was approved by the Food and Drug Administration in 1988 (11).…”

Matrix metalloproteinases in impaired wound healing

“…Tetracyclines Minocycline Inhibition of MMP-1, -2, -3, -8, and -9, and iNOS 41 Gastrointestinal toxicity; 44 possibility of development of antibiotic-resistant strains of bacteria 43…”

“…Tetracyclines have also been tested for the treatment of chronic wounds, and most of the initial studies focused on two semi-synthetic tetracyclines: minocycline and doxycycline. [42][43][44][45] Minocycline is an antibiotic semi-synthetically synthesized from the original tetracyclines, which was shown by in vivo and in vitro studies to inhibit the gelatinases MMP-2 and MMP-9, the collagenases MMP-1, MMP-8, and MMP-13, and stromelysin (MMP-3), apparently through downregulation of expression of these enzymes and with special sensitivity for MMP-9. 46 In addition, minocycline inhibits the inducible version of nitric oxide synthase (iNOS), a proinflammatory enzyme that is known to induce catabolic events mediated by IL-1β and to upregulate expression of MMPs.…”

“…47 Doxycycline is a more potent inhibitor of MMPs than original tetracyclines and has several advantages over minocycline, particularly better pharmacokinetics, making it safer for the patient. 44 It was reported to inhibit MMP-1 and MMP-8 with half maximal inhibitory concentration values of 25 mM and 300 mM, respectively, and to inhibit both the activity and the secretion of MMP-2 and MMP-9. 32,42,48 Several clinical trials have reported beneficial effects of doxycycline for treatment of chronic wounds, which have been associated with inhibition of MMPs.…”

“…Inhibition of MMP-1, -2, -3, -8, -9, -10, -11, -13, MT-MMPs, and neutrophil elastase [42][43][44] Not well studied…”