Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy

Abstract

This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

Anti‐inflammatory and anti‐resorptive efficacy of adrenergic blockers on late replanted rat incisors

“…TRAP is a resorptive enzyme found in the ruffled border of the osteoclast membrane and is considered a specific marker of osteoclast differentiation . The suppression of osteoclastic formation is reported to be a result of the pharmacological blockade of α1‐AR and β2‐AR on the surfaces of osteoblasts, which prevents their binding to adrenergic neurotransmitters and reduces the expression of RANKL, the main inducer of osteoclastogenesis and osteoclastic activity . Similar effects were found by Okada et al and Rodrigues et al, who reported a reduction in the number of osteoclasts and the prevention of alveolar bone loss in rats with experimental periodontitis after the blockade of β‐receptors by the intraperitoneal or oral administration of propranolol.…”

“…Similar effects were found by Okada et al and Rodrigues et al, who reported a reduction in the number of osteoclasts and the prevention of alveolar bone loss in rats with experimental periodontitis after the blockade of β‐receptors by the intraperitoneal or oral administration of propranolol. In addition, these drugs have been shown to reduce the levels of IL‐1β (Ph and Pr), IL‐6 (Ph), IL‐8 (Ph), TNF‐α (Pr), and RANKL (Pr) in gingival tissues and increase the expression of OPG (Pr) . It is noteworthy, however, that the beneficial effects observed at these dosages on osteoclastogenesis in this study were not enough to produce a significant improvement in periodontal repair or the formation and resorption of bone, cementum, and dentin.…”

“…These neurotransmitters in turn bind to α1‐ (α1‐AR) and β2‐adrenergic (β2‐AR) receptors present on the surfaces of osteoblasts and other PDL cells, which causes an increase in RANKL expression, the stimulation of osteoclastic differentiation, the regulation of immune cell proliferation, and the production of cytokines . On the other hand, the blockade of α1‐AR and β2‐AR in periodontal tissue by phentolamine and propranolol, respectively, has been shown to reduce the levels of inflammatory cytokines, inhibit the formation of osteoclasts, and prevent bone loss in the inflamed periodontium …”

Periodontitis as another comorbidity associated with psoriasis: A case‐control study

“…In addition, because it is an alteration with systemic triggers for the individual over a prolonged period of time, it is suggested that immunological changes (exacerbation in the expression of cytokines), endocrine, and behavioral disorders (poor oral hygiene, smoking, and other deleterious habits) predispose to the susceptibility to both diseases …”

Impact of chronic stress on periodontal health

“…For Lu et al [60], this rapid evolution is because of the stimulation of the stress-induced ANS stimulation, which results in the release of neurotransmitters (catecholamine neurotransmitter, epinephrine). These neurotransmitters are capable of binding to a1-adrenergic (a1-AR) receptors present on the surface of periodontal cells, thus decreasing their biological activity and causing a massive release of inflammatory factors [60].…”