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The H2S-releasing naproxen derivative, ATB-346, inhibits alveolar bone loss and inflammation in rats with ligature-induced periodontitis.

Herrera BS, Coimbra LS, da Silva AR, Teixeira SA, Costa SK, Wallace JL, Spolidorio LC, Muscara MN - Med Gas Res (2015)

Bottom Line: 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.Significant damage and increased MPO contents were only found in the stomachs of the naproxen-treated animals.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.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Gingival IL-1β and IL-6 contents are increased in rats with ligature-induced periodontitis but counterregulated by treatment with either naproxen or ATB-346. IL-1β, IL-6 and IL-10 contents measured in rat gingival samples obtained from the different treatment groups. *P < 0.05 and ***P < 0.001 vs. Sham; #P < 0.05; ##P < 0.01 and ###P < 0.001 vs. Vehicle (n = 6 for each group).
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Fig3: Gingival IL-1β and IL-6 contents are increased in rats with ligature-induced periodontitis but counterregulated by treatment with either naproxen or ATB-346. IL-1β, IL-6 and IL-10 contents measured in rat gingival samples obtained from the different treatment groups. *P < 0.05 and ***P < 0.001 vs. Sham; #P < 0.05; ##P < 0.01 and ###P < 0.001 vs. Vehicle (n = 6 for each group).

Mentions: As shown in Figure 3, the presence of ligature induced significant increases in the gingival contents of IL-1β and IL-6, as well as decreased IL-10, in comparison with the Sham animals (IL-1β: 134.8 ± 29.1 vs. 15.3 ± 1.5 pg/mg of protein; IL-6: 13.7 ± 1.2 vs. 5.6 ± 0.5 pg/mg of protein; IL-10: 0.6 ± 0.2 vs. 2.9 ± 0.4 pg/mg of protein; P < 0.001 for all the three cytokines). Treatment with either naproxen, ATB-346 or Na2S resulted in significant decrease of gingival IL-1β contents (61.4 ± 7.8, 33.3 ± 6.0 and 31.2 ± 2.6 pg/mg of protein, respectively; panel A), but only naproxen and ATB-346 resulted in decreased IL-6 (6.8 ± 0.8 and 6.1 ± 1.0, respectively; panel B). Regarding IL-10 contents, none of the treatments affected the ligature-induced decrease; panel C).Figure 3


The H2S-releasing naproxen derivative, ATB-346, inhibits alveolar bone loss and inflammation in rats with ligature-induced periodontitis.

Herrera BS, Coimbra LS, da Silva AR, Teixeira SA, Costa SK, Wallace JL, Spolidorio LC, Muscara MN - Med Gas Res (2015)

Gingival IL-1β and IL-6 contents are increased in rats with ligature-induced periodontitis but counterregulated by treatment with either naproxen or ATB-346. IL-1β, IL-6 and IL-10 contents measured in rat gingival samples obtained from the different treatment groups. *P < 0.05 and ***P < 0.001 vs. Sham; #P < 0.05; ##P < 0.01 and ###P < 0.001 vs. Vehicle (n = 6 for each group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4353461&req=5

Fig3: Gingival IL-1β and IL-6 contents are increased in rats with ligature-induced periodontitis but counterregulated by treatment with either naproxen or ATB-346. IL-1β, IL-6 and IL-10 contents measured in rat gingival samples obtained from the different treatment groups. *P < 0.05 and ***P < 0.001 vs. Sham; #P < 0.05; ##P < 0.01 and ###P < 0.001 vs. Vehicle (n = 6 for each group).
Mentions: As shown in Figure 3, the presence of ligature induced significant increases in the gingival contents of IL-1β and IL-6, as well as decreased IL-10, in comparison with the Sham animals (IL-1β: 134.8 ± 29.1 vs. 15.3 ± 1.5 pg/mg of protein; IL-6: 13.7 ± 1.2 vs. 5.6 ± 0.5 pg/mg of protein; IL-10: 0.6 ± 0.2 vs. 2.9 ± 0.4 pg/mg of protein; P < 0.001 for all the three cytokines). Treatment with either naproxen, ATB-346 or Na2S resulted in significant decrease of gingival IL-1β contents (61.4 ± 7.8, 33.3 ± 6.0 and 31.2 ± 2.6 pg/mg of protein, respectively; panel A), but only naproxen and ATB-346 resulted in decreased IL-6 (6.8 ± 0.8 and 6.1 ± 1.0, respectively; panel B). Regarding IL-10 contents, none of the treatments affected the ligature-induced decrease; panel C).Figure 3

Bottom Line: 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.Significant damage and increased MPO contents were only found in the stomachs of the naproxen-treated animals.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.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus