Pharmacological Research 48 (2003) 437–443 Effects of valeryl salicylate, a COX-1 inhibitor, on models of acute inflammation in mice Jarbas M. Siqueira-Junior a , Rodrigo R. Peters a,b , Artur J. de Brum-Fernandes c , Rosa M. Ribeiro-do-Valle a,∗ a Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82, CEP: 88015-420, Florianópolis-SC, Brazil b Grupnat Natural Products Research, Universidade do Sul de Santa Catarina, Tubarão-SC, Brazil c Department of Medicine (Rheumatic Disease Unit), Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Canada Accepted 12 May 2003 Abstract The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2 mg per ear; 20 l) or croton oil (1 mg per ear; 20 l) to the inner surface of the left ear and the change in the ear’s thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after l h at doses of 1.5–45 g per ear; however, only at the dose of 45 g per ear was it able to significantly reduce the croton oil-induced oedema at 6 h. Paw oedema was induced by the injection of 25 l of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72 h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2 h, in the early phase (0–4 h), and the other, occurring at 48 h after carrageenan injection, in the late phase (24–72 h). The pre-treatment with VS significantly reduced the paw oedema at 2 h, the same effect observed with celecoxib and indomethacin treatments. At 24 h, VS did not inhibit oedema but significantly increased it mainly at 48 h after carrageenan injection. These results showed that VS was pharmacologically active in these models and suggest that COX-1 may participate in the early and late phases of inflammation in the models studied. © 2003 Elsevier Ltd. All rights reserved. Keywords: Valeryl salicylate; COX-1; Paw oedema; Mice 1. Introduction Valeryl salicylate (VS) has been described as an irre- versible inhibitor of cyclooxygenase, which exhibits four- to five-fold selectivity toward cyclooxygenase-1 [1,2]. Cyclooxygenases (COX) are isoenzymes present in many tissues. According to the original concept COX-1, a consti- tutive isoenzyme, is involved in the maintenance of essential physiological functions such as platelet aggregation, cyto- protection in the stomach and maintenance of normal kidney functions [3–7]. COX-2 has been shown to be induced at inflammatory sites [3,8] and it can be induced by proinflam- matory cytokines, endotoxins, mitogens and tumour promot- ers [9–13]. In addition, COX-2 is constitutively expressed in the kidney and brain [14,15]. ∗ Corresponding author. Tel.: +55-48-331-9491; fax: +55-48-222-4164. E-mail addresses: jarbasms@farmaco.ufsc.br (J.M. Siqueira-Junior), ribeiro@farmaco.ufsc.br (R.M. Ribeiro-do-Valle). The currently available non-steroidal anti-inflammatory drugs (NSAIDs) in clinical use act by inhibiting the activity of the cyclooxygenase enzymes [16–18]. The capacity of NSAIDs to inhibit COX-1 is related to their adverse effects such as gastric toxicity [19]. This suggests that selective inhibition of COX-2 may be a better therapy in inflammation. Several selective COX-2 inhibitors have been developed that demonstrate anti-inflammatory effects with an improved side effect profile [20–23]. Carrageenan-induced paw oedema, arachidonic acid- induced ear oedema and croton oil-induced ear oedema are common models used to study the anti-inflammatory activity of NSAIDs [9,24]. Topical application of arachidonic acid to the mouse ear produces a short-lived oedema response with a rapid onset that was associated with marked increases in levels of prostaglandins; whereas topical application of tetradecanoylphorbol 13-acetate (TPA—a derivative of cro- ton oil), produced a longer-lasting oedema associated with marked influx of neutrophils [24]. Carrageenan-induced 1043-6618/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1043-6618(03)00188-9