Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Medical Gas Research
Published in: Medical Gas Research 1/2015

Open Access 01-12-2015 | Research

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

Authors: Bruno Schneider Herrera, Leila Santana Coimbra, Agatha Ribeiro da Silva, Simone Aparecida Teixeira, Soraia Katia Pereira Costa, John Lawrence Wallace, Luis Carlos Spolidorio, Marcelo Nicolas Muscara

Published in: Medical Gas Research | Issue 1/2015

Login to get access

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.
Literature
1.
Page RC, Eke PI. Case definitions for use in population-based surveillance of periodontitis. J Periodontol. 2007;78(7 Suppl):1387–99.CrossRefPubMed
2.
Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases. J Dent Res. 2003;82:82–90.CrossRefPubMed
3.
Kantarci A, Hasturk H, Van Dyke TE. Host-mediated resolution of inflammation in periodontal diseases. Periodontology 2000. 2006;40:144–63.CrossRefPubMed
4.
The J, Ebersole JL. Rheumatoid factor (RF) distribution in periodontal disease. J Clin Immunol. 1991;11:132–42.CrossRefPubMed
5.
Boggess KA, Lieff S, Murtha AP, Moss K, Beck J, Offenbacher S. Maternal periodontal disease is associated with an increased risk for preeclampsia. Obstet Gynecol. 2003;101:227–31.CrossRefPubMed
6.
Offenbacher S, Boggess KA, Murtha AP, Jared HL, Lieff S, McKaig RG, et al. Progressive periodontal disease and risk of very preterm delivery. Obstet Gynecol. 2006;107:29–36.CrossRefPubMed
7.
Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol. 1996;67(10 Suppl):1085–93.CrossRefPubMed
8.
Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, et al. The american journal of cardiology and journal of periodontology editors’ consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontol. 2009;80:1021–32.CrossRefPubMed
9.
Fredman G, Oh SF, Ayilavarapu S, Hasturk H, Serhan CN, Van Dyke TE. Impaired phagocytosis in localized aggressive periodontitis: rescue by resolvin E1. PLoS One. 2011;6:e24422.CrossRefPubMedCentralPubMed
10.
Hasturk H, Kantarci A, Ohira T, Arita M, Ebrahimi N, Chiang N, et al. RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis. FASEB J. 2006;20:401–3.PubMed
11.
Morton RS, Dongari-Bagtzoglou AI. Cyclooxygenase-2 is upregulated in inflamed gingival tissues. J Periodontol. 2001;72:461–9.CrossRefPubMed
12.
Offenbacher S, Heasman PA, Collins JG. Modulation of host PGE2 secretion as a determinant of periodontal disease expression. J Periodontol. 1993;64(5 Suppl):432–44.CrossRefPubMed
13.
14.
Holzhausen M, Spolidorio DM, Muscara MN, Hebling J, Spolidorio LC. Protective effects of etoricoxib, a selective inhibitor of cyclooxygenase-2, in experimental periodontitis in rats. J Periodontal Res. 2005;40:208–11.CrossRefPubMed
15.
Holzhausen M, Rossa Junior C, Marcantonio Junior E, Nassar PO, Spolidorio DM, Spolidorio LC. Effect of selective cyclooxygenase-2 inhibition on the development of ligature-induced periodontitis in rats. J Periodontol. 2002;73:1030–6.CrossRefPubMed
16.
Salvi GE, Lang NP. The effects of non-steroidal anti-inflammatory drugs (selective and non-selective) on the treatment of periodontal diseases. Curr Pharm Des. 2005;11:1757–69.CrossRefPubMed
17.
Howell TH, Jeffcoat MK, Goldhaber P, Reddy MS, Kaplan ML, Johnson HG, et al. Inhibition of alveolar bone loss in beagles with the NSAID naproxen. J Periodontal Res. 1991;26:498–501.CrossRefPubMed
18.
Aras H, Caglayan F, Guncu GN, Berberoglu A, Kilinc K. Effect of systemically administered naproxen sodium on clinical parameters and myeloperoxidase and elastase-like activity levels in gingival crevicular fluid. J Periodontol. 2007;78:868–73.CrossRefPubMed
19.
Tsai CC, Hong YC, Chen CC, Wu YM. Measurement of prostaglandin E2 and leukotriene B4 in the gingival crevicular fluid. J Dent. 1998;26:97–103.CrossRefPubMed
20.
Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4–15.CrossRefPubMedCentralPubMed
21.
Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiol Rev. 2008;88:1547–65.CrossRefPubMed
22.
Muscara MN, Wallace JL. COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function. Cardiovasc Hematol Agents Med Chem. 2006;4:155–64.CrossRefPubMed
23.
Distrutti E, Sediari L, Mencarelli A, Renga B, Orlandi S, Russo G, et al. 5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity. J Pharmacol Exp Ther. 2006;319:447–58.CrossRefPubMed
24.
Fiorucci S, Orlandi S, Mencarelli A, Caliendo G, Santagada V, Distrutti E, et al. Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis. Br J Pharmacol. 2007;150:996–1002.CrossRefPubMedCentralPubMed
25.
Wallace JL, Caliendo G, Santagada V, Cirino G. Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br J Pharmacol. 2010;159:1236–46.CrossRefPubMedCentralPubMed
26.
Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology. 2007;132:261–71.CrossRefPubMed
27.
Wallace JL. Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol Sci. 2007;28:501–5.CrossRefPubMed
28.
Blackler R, Syer S, Bolla M, Ongini E, Wallace JL. Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS One. 2012;7:e35196.CrossRefPubMedCentralPubMed
29.
Campolo M, Esposito E, Ahmad A, Di Paola R, Wallace JL, Cuzzocrea S. A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury. FASEB J. 2013;27:4489–99.CrossRefPubMed
30.
Ekundi-Valentim E, Mesquita FP, Santos KT, de Paula MA, Florenzano J, Zanoni CI, et al. A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis. Med Gas Res. 2013;3:24.CrossRefPubMedCentralPubMed
31.
Irie K, Ekuni D, Yamamoto T, Morita M, Yaegaki K, Ii H, et al. A single application of hydrogen sulphide induces a transient osteoclast differentiation with RANKL expression in the rat model. Arch Oral Biol. 2009;54(8):723–9.CrossRefPubMed
32.
Irie K, Ekuni D, Tomofuji T, Endo Y, Kasuyama K, Yaegaki K, et al. Combined effects of hydrogen sulfide and lipopolysaccharide on osteoclast differentiation in rats. J Periodontol. 2012;83:522–7.CrossRefPubMed
33.
Toker H, Balci Yuce H, Goze F, Ozdemir H, Akpinar A, Bostanci V. The effects of hydrogen sulphide on alveolar bone loss in periodontitis. Minerva Stomatol. 2014;63:103–10.PubMed
34.
Sallay K, Sanavi F, Ring I, Pham P, Behling UH, Nowotny A. Alveolar bone destruction in the immunosuppressed rat. J Periodontal Res. 1982;17:263–74.CrossRefPubMed
35.
Wilensky A, Gabet Y, Yumoto H, Houri-Haddad Y, Shapira L. Three-dimensional quantification of alveolar bone loss in Porphyromonas gingivalis-infected mice using micro-computed tomography. J Periodontol. 2005;76:1282–6.CrossRefPubMed
36.
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.CrossRefPubMed
37.
Wallace JL, McCafferty DM, Carter L, McKnight W, Argentieri D. Tissue-selective inhibition of prostaglandin synthesis in rat by tepoxalin: anti-inflammatory without gastropathy. Gastroenterology. 1993;105:1630–6.PubMed
38.
Herrera BS, Martins-Porto R, Campi P, Holzhausen M, Teixeira SA, Mendes GD, et al. Local and cardiorenal effects of periodontitis in nitric oxide-deficient hypertensive rats. Arch Oral Biol. 2011;56:41–7.CrossRefPubMedCentralPubMed
39.
Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontology 2000. 1997;14:9–11.CrossRefPubMed
40.
Herrera BS, Martins-Porto R, Maia-Dantas A, Campi P, Spolidorio LC, Costa SK, et al. iNOS-derived nitric oxide stimulates osteoclast activity and alveolar bone loss in ligature-induced periodontitis in rats. J Periodontol. 2011;82:1608–15.CrossRefPubMedCentralPubMed
41.
Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LA, et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21:325–32.CrossRefPubMedCentralPubMed
42.
Ciancio SG. Systemic medications: clinical significance in periodontics. J Clin Periodontol. 2002;29 Suppl 2:17–21.PubMed
43.
Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92:791–896.CrossRefPubMed
44.
45.
Flannigan KL, Ferraz JG, Wang R, Wallace JL. Enhanced synthesis and diminished degradation of hydrogen sulfide in experimental colitis: a site-specific, pro-resolution mechanism. PLoS One. 2013;8:e71962.CrossRefPubMedCentralPubMed
46.
Dufton N, Natividad J, Verdu EF, Wallace JL. Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe. Scientific Reports. 2012;2:499.CrossRefPubMedCentralPubMed
47.
48.
El-Sharkawy H, Aboelsaad N, Eliwa M, Darweesh M, Alshahat M, Kantarci A, et al. Adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 fatty acids and low-dose aspirin. J Periodontol. 2010;81(11):1635–43.CrossRefPubMed
49.
50.
Wang R. Signaling pathways for the vascular effects of hydrogen sulfide. Curr Opin Nephrol Hypertens. 2011;20:107–12.CrossRefPubMed
51.
52.
Matsunami M, Kirishi S, Okui T, Kawabata A. Chelating luminal zinc mimics hydrogen sulfide-evoked colonic pain in mice: possible involvement of T-type calcium channels. Neuroscience. 2011;181:257–64.CrossRefPubMed
53.
Chattopadhyay M, Kodela R, Nath N, Barsegian A, Boring D, Kashfi K. Hydrogen sulfide-releasing aspirin suppresses NF-kappaB signaling in estrogen receptor negative breast cancer cells in vitro and in vivo. Biochem Pharmacol. 2012;83:723–32.CrossRefPubMed
54.
Caro AA, Thompson S, Tackett J. Increased oxidative stress and cytotoxicity by hydrogen sulfide in HepG2 cells overexpressing cytochrome P450 2E1. Cell Biol Toxicol. 2011;27:439–53.CrossRefPubMedCentralPubMed
55.
Lee SK, Chung JH, Choi SC, Auh QS, Lee YM, Lee SI, et al. Sodium hydrogen sulfide inhibits nicotine and lipopolysaccharide-induced osteoclastic differentiation and reversed osteoblastic differentiation in human periodontal ligament cells. J Cell Biochem. 2013;114:1183–93.CrossRefPubMed
Metadata
Title
The H2S-releasing naproxen derivative, ATB-346, inhibits alveolar bone loss and inflammation in rats with ligature-induced periodontitis
Authors
Bruno Schneider Herrera
Leila Santana Coimbra
Agatha Ribeiro da Silva
Simone Aparecida Teixeira
Soraia Katia Pereira Costa
John Lawrence Wallace
Luis Carlos Spolidorio
Marcelo Nicolas Muscara
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Medical Gas Research / Issue 1/2015
Electronic ISSN: 2045-9912
DOI
https://doi.org/10.1186/s13618-015-0025-3

Other articles of this Issue 1/2015

Medical Gas Research 1/2015 Go to the issue

Research

Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model

Commentary

All the right moves: the need for the timely use of hyperbaric oxygen therapy for treating TBI/CTE/PTSD

Review

Hyperbaric oxygen therapy in China

Research

Stimulation of human damaged sperm motility with hydrogen molecule

Research

Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential

Research

Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits