title: The H2S-releasing naproxen derivative, ATB-346, inhibits alveolar bone loss and inflammation in rats with ligature-induced periodontitis.
abstract: BACKGROUND
  In experimental periodontitis, non-steroidal antiinflammatory drugs (NSAIDs) effectively inhibit the resultant alveolar bone loss. However, their deleterious gastric effects, observed in both animals and humans, dramatically limit their long-term use. It has been proven that the addition of a hydrogen sulfide (H2S)-releasing moiety to classical NSAID structures results in antiinflammatory compounds with improved gastric safeness. In this way, we decided to compare the effects of naproxen with its H2S-releasing derivative ATB-346 on ligature-induced periodontitis in rats.
  
  
  METHODS
  Male Holtzman rats had a cotton ligature placed subgingivally around the lower right first molar during 7 days. During this period, groups of animals were daily treated with Na2S (a spontaneous H2S donor) or equimolar oral doses of naproxen (10 mg/kg) or ATB-346 (16 mg/kg). The mandibles were finally collected for histological analysis, radiographical measurements of alveolar bone loss and micro-computed tomography (μCT) analysis. Interleukin (IL)-1β, IL-6 and IL-10 were quantified in gingiva samples, and the stomachs were also collected for scoring of tissue damage and measurement of myeloperoxidase (MPO, a marker of granulocyte infiltration).
  
  
  RESULTS
  Ligature-induced bone loss was significantly inhibited by all the treatments, although only ATB-346 treatment resulted in significant inhibition of bone defect and other histological characteristics (such as flatness of the gingival epithelium, chronic inflammatory cell infiltration and loss of connective tissue in the gingival papillae). Both naproxen and ATB-346 inhibited the increase of gingival IL-1β and IL-6 secondary to periodontitis, but IL-10 was unaffected. Significant damage and increased MPO contents were only found in the stomachs of the naproxen-treated animals.
  
  
  CONCLUSIONS
  The H2S-releasing moiety in the ATB-346 compound not only does not impair the effects of the parent naproxen on periodontitis, but also improves bone quality and prevents the gastric mucosa damage due to prostaglandin inhibition, thus configuring a potentially new adjuvant therapy for periodontal diseases.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil ; Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil.
authors.forename: Bruno Schneider
authors.initials: BS
authors.lastname: Herrera
authors.affiliation: Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil.
authors.forename: Leila Santana
authors.initials: LS
authors.lastname: Coimbra
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil.
authors.forename: Agatha Ribeiro
authors.initials: AR
authors.lastname: da Silva
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil.
authors.forename: Simone Aparecida
authors.initials: SA
authors.lastname: Teixeira
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil.
authors.forename: Soraia Katia Pereira
authors.initials: SK
authors.lastname: Costa
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON Canada.
authors.forename: John Lawrence
authors.initials: JL
authors.lastname: Wallace
authors.affiliation: Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil.
authors.forename: Luis Carlos
authors.initials: LC
authors.lastname: Spolidorio
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil.
authors.forename: Marcelo Nicolas
authors.initials: MN
authors.lastname: Muscara
keywords: ATB-346; Bone loss; H2S-releasing NSAID; Inflammation; Periodontitis