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

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.

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

“…In agreement with our data, Zanardo and co-workers [48] have shown that spontaneous H2S donors, such as Na2S, NaHS and LR, markedly inhibited carrageenan-induced leukocyte adhesion and infiltration in a rodent air pouch model. Similar results were obtained by Ekundi-Valentim and co-workers [16,20] in the model of carrageenan-induced synovitis in rats, and by Fiorucci and coworkers [49] in the acetyl salycilic acid-induced gastric injury in rats. Reduced expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1, P-selectin, E-selectin in both endothelium and leukocytes has been suggested as the underlying mechanism of H2S-mediated inhibition of leukocyte influx [40,[48][49][50].…”

“…However, the use of slow-releasing H2S donors (such as SG-1002, diallyl trisulfide and GYY4137) and hybrid H2S-releasing non steroidal anti-inflammatory compounds (such as the naproxen derivative strengthens the beneficial therapeutical effects of H2S in articular inflammation [20], colorectal cancer [21], periodontitis [22] and pain [23] with additional gastrointestinal safety [24]. More recently, low serum levels of H2S has been associated with psoriasis [25], a disease often associated with pruritus [26].…”

Peripheral Neurokinin-1 Receptors Contribute to Kaolin-Induced Acute Monoarthritis in Rats

“…In combination with CGN, kaolin causes moderate arthritis, characterized by rapid knee swelling concomitantly with increased blood flow, angiogenesis, allodynia, and both secondary mechanical and thermal hyperalgesia [10,11,12,13,14]. Our previous studies show that intra-articular injection of CGN alone causes knee inflammation and secondary tactile allodynia by triggering a wide inflammatory cascade, including increased NO production and protein oxidation, that may maintain an ongoing state of inflammation in the joint [15,16]. CGN injection into the rat temporomandibular joint induces a marked time-dependent plasma extravasation associated with neutrophil accumulation and increased IL-1β levels [17].…”

Estudo dos efeitos do composto GYY-4137, um doador de sulfeto de hidrogênio (H₂S), na sinovite aguda induzida por carragenina na articulação temporomandibular de ratos.

“…A administração de ATB-346, um doador de H 2 S derivado do naproxeno, evidenciou atividade anti-inflamatória na sinovite induzida por CGN no joelho de ratos e foi capaz de reduzir os efeitos gástricos deletérios do naproxeno (Ekundi-Valentim et al, 2013). Doadores de H 2 S derivados do diclofenaco também exibiram atividade anti-inflamatória em modelo de choque endotóxico e no edema de pata induzido pela CGN Sidhapuriwala et al, 2007;Wallace et al, 2007).…”