Adenosine A2A Receptor Stimulation: A New Strategy for the Treatment of Periodontitis
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 13, Issue 5
Abstract
Periodontitis is an unpleasant clinical condition in which an exaggerated inflammatory reaction occurs in the extravascular gingival tissue. Inflammatory cells release cytokines that amplify tissue inflammation and create the condition for periodontal tissue damage. Adenosine is a mediator that is released under several pathological conditions including ischemia and inflammation and participates in the regulation of inflammatory reaction. Among the several adenosine receptors, the adenosine A2A subtype plays a key role in resolving gingival inflammation and in protecting the periodontal tissues from damage. PDRN (polydeoxyribonuclotide) binds selectively the A2A subtype and exerts curative effect, suggesting that adenosine A2A receptor stimulation might be an innovative strategy for the treatment of periodontitis. Periodontitis is common diseases of the oral cavity [1]. It is a devastating inflammatory condition that takes place at the level of the soft and hard tissues surrounding the teeth [2] and it is one of the leading cause of teeth loss worldwide [3]. Modifiable and diffuse risk factors (e.g., elevated blood pressure, increased blood cholesterol, metabolic syndrome) and unhealthy behaviors (poor physical activity, smoking and consumption of high fat rich food) may significantly influence the development of the disease [4]. An exaggerated inflammatory reaction represents the hallmark of the periodontitis pathogenesis. Bacteria overloading in the gingival sulcus induces accumulation of Polymorphonuclear Neutrophils (PMNs) and monocytes. PMNs and monocytes work in concert with epithelial cells of gingivae to cause the production of Interleukin (IL)-1β, Tumour Necrosis Factor α (TNF-α), IL-6 and High Mobility Group Box 1 protein (HMGB-1). These pro-inflammatory cytokines trigger the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) that favors the adhesion and accumulation of the inflammatory leukocytes (PMNs and monocytes) to the endothelium and augment the cross-talk between the several cell types leading to the leakage of leukocytes into the infected tissues [5]. This cascade of events causes macrophages, that have been recruited in the inflammatory zone, to release Prostaglandin 2 (PGE2). This prostanoid and the inflammatory cytokine IL-1β prompt the accumulation of PMNs and monocytes to endothelial cells, thus amplifying and empowering inflammation; finally, these two mediators together with IL-6 and TNF-α, cause osteoclasts to stimulate and reabsorb the alveolar bone [6,7]. Besides inflammation, apoptosis has been also shown to have a role in periodontitis: infact the pro-apoptotic protein BAX-1 is enhanced while the anti-apoptotic protein Bcl-2 is reduced, thus leading to an enhanced destruction of the alveolar bone. Adenosine is a mediator that is released under several pathological conditions including ischemia and inflammation and participates in the regulation of inflammatory reaction [8]. Interestingly it has been proposed that adenosine may have an anti-inflammatory role. Adenosine is produced both in the intracellular and extracellular compartments through dephosphorylation of Adenosine Monophosphate (AMP) by ecto-5’-nuclotidates; then it is transformed to inosine via the activity of adenosine deaminase and finally degraded to uric acid [8]. Adenosine engages on cell membrane G protein coupled adenosine receptors that are localized in almost all mammalian cells. Four types of adenosine receptors have been identified and indicated as A1, A2A, A2B and A3.These receptors differ in affinity for adenosine and have a different level of expression in the several cell types. It has been previously reported that adenosine receptors are present in both human gingival cells and fibroblasts and that their up-regulation or down-regulation may serve as signal mechanisms to orchestrate the production of other inflammatory mediators [9].Indeed, previous experimental work has suggested that the expression of A2A, and A2B receptors are enhanced in periodontitis while A3 expression is reduced and A1 expression is unchanged. Regarding the finalistic meaning of these changes, it is generally accepted that over-expression of the A2A, and A2B receptors may serve as a brake to halt the inflammatory cascade [9]. This leads to hypothesize that activation of one or both of these two types of Adenosine Receptors (A2A, and A2B) may represent a rational strategy to design new drugs for the treatment of periodontitis.
Authors and Affiliations
Giacomo Picciolo, Natasha Irrera, Giuseppe Picciolo, Francesco Squadrito
Keywords
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- EP ID EP593770
- DOI 10.26717/BJSTR.2019.13.002457
- Views 146
- Downloads 0
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