Herrera Bruno Schneider, Coimbra Leila Santana, da Silva Agatha Ribeiro, Teixeira Simone Aparecida, Costa Soraia Katia Pereira, Wallace John Lawrence, Spolidorio Luis Carlos, Muscara Marcelo Nicolas
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.
Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil.
Med Gas Res. 2015 Feb 27;5:4. doi: 10.1186/s13618-015-0025-3. eCollection 2015.
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.
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).
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.
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.
在实验性牙周炎中，非甾体抗炎药（NSAIDs）可有效抑制由此导致的牙槽骨丧失。然而，在动物和人类中均观察到它们对胃的有害作用，这极大地限制了其长期使用。已证实，在经典NSAID结构中添加释放硫化氢（H2S）的部分可产生胃安全性更高的抗炎化合物。因此，我们决定比较萘普生及其释放H2S的衍生物ATB-346对大鼠结扎诱导的牙周炎的影响。
雄性霍尔茨曼大鼠在7天内于右下第一磨牙龈下放置棉线结扎。在此期间，将动物分组，每天用Na2S（一种自发的H2S供体）或等摩尔口服剂量的萘普生（10 mg/kg）或ATB-346（16 mg/kg）进行治疗。最后收集下颌骨用于组织学分析、牙槽骨丧失的影像学测量和微计算机断层扫描（μCT）分析。对牙龈样本中的白细胞介素（IL）-1β、IL-6和IL-10进行定量分析，同时收集胃组织用于组织损伤评分和髓过氧化物酶（MPO，粒细胞浸润的标志物）测量。
所有治疗均显著抑制了结扎诱导的骨丧失，尽管只有ATB-346治疗显著抑制了骨缺损和其他组织学特征（如牙龈上皮平整度、慢性炎性细胞浸润和牙龈乳头结缔组织丧失）。萘普生和ATB-346均抑制了牙周炎继发的牙龈IL-1β和IL-6升高，但IL-10未受影响。仅在萘普生治疗的动物胃中发现了明显的损伤和MPO含量增加。
ATB-346化合物中释放H2S的部分不仅不会削弱母体萘普生对牙周炎的作用，还能改善骨质并防止因前列腺素抑制导致的胃黏膜损伤，从而构成一种潜在的牙周疾病新辅助治疗方法。
