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

Eduardo Ekundi-Valentim,Filiphe Pn Mesquita,Juliana Florenzano,Heloisa Ha Ferreira,Karen T Santos,Gilberto De Nucci,Leandro Rodrigues,Simone A Teixeira,Soraia Kp Costa,John L Wallace,John L Wallace,Marcelo N Muscará,Cristiane I Zanoni,Marco A De Paula

doi:10.1186/2045-9912-3-24

Abstract

BackgroundNon-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model.MethodsMale Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing.ResultsAt the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance.ConclusionThe presence of a H2S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H2S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.

Highlights

Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, gastric effects limit their long-term use
(P < 0.001) 4 h after the carrageenan injection, no other significant differences were observed between naproxen and ATB-346 when administered at equimolar doses
The i.art. injection of carrageenan resulted in significant impairment of the normal walking pattern, as evidenced by the increased gait score observed after 3 or 5 h (Figure 2), and pre-treatment of the animals with either naproxen (3.0 and 10 mg/kg; n = 8) or ATB-346 (4.8 and 16 mg/kg) 30 min before carrageenan, resulted in significant decrease of this score, except for the 4.8 mg/kg ATB-346 treated group evaluated at the 5 h time-point

Summary

Introduction

Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, gastric effects limit their long-term use. NSAIDs are the most widely used drugs for the relief of pain, swelling and stiffness of the joints in RA [2]; in addition to the higher risks of renal and cardiovascular occurrences [3], the chronic use of NSAIDs results in clinically significant gastrointestinal ulceration and bleeding [4] The mechanisms underlying these gastric damage events include both direct toxic effects of the NSAIDs on the epithelial cells, and others related to the prostaglandin synthesis inhibition, such as the reduction of mucus and bicarbonate secretion [5] and the increased neutrophil adherence and activation [6]. The anti-inflammatory properties of exogenously administered H2S have been observed in several experimental models such as carrageenan-induced paw edema in rats [10], myocardial ischemia-reperfusion injury in pigs [11], arthritis [12,13,14] and lung injury [15] and asthma [16] in mice

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