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PAI-19-2 Master Research article Singlet oxygen scavenging activity of non- steroidal anti-inflammatory drugs David Costa, Ana Gomes, José L.F.C. Lima, Eduarda Fernandes REQUIMTE, Departamento de Química-Física, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal 1 It has long been known that singlet oxygen ( O2) is generated during inflammatory processes. 1 Once formed in substantial amounts, O2 may have an important role in mediating the destruction 1 of infectious agents during host defense. On the other hand, O2 is capable of damaging almost all biological molecules and is particularly genotoxic, which gives a special relevance to the scavenging of this ROS throughout anti-inflammatory treatments. Considering that the use of non- steroidal anti-inflammatory drugs (NSAIDs) constitutes a first approach in the treatment of persistent inflammatory processes (due to their ability to inhibit cyclooxygenase), a putative 1 scavenging activity of NSAIDs for O2 would also represent a significant component of their 1 therapeutic effect. The aim of the present study was to evaluate the scavenging activity for O2 by several chemical families of NSAIDs. The results suggested that the pyrazole derivatives (dipyrone 1 and aminopyrine) are, by far, the most potent scavengers of O2 (much more potent compared to the other tested NSAIDs), displaying IC 50 -values in the low micromolar range. There was a lack of activity for most of the arylpropionic acid derivatives tested, with only naproxen and indoprofen displaying residual activities, as for the oxazole derivative, oxaprozin. On the other hand, the pyrrole derivatives (tolmetin and ketorolac), the indolacetic acid derivatives (indomethacin, and etodolac), as well as sulindac and its metabolites (sulindac sulfide and sulindac sulfone) displayed scavenging activity in the high micromolar range. Thus, the scavenging effect observed for dipyrone and aminopyrine will almost certainly contribute to their healing effect in the treatment of prolonged or chronic inflammation, while that of the other studied NSAIDs may have a lower contribution, though these assumptions still require further in vivo validation. Keywords: NSAIDs, singlet oxygen, endoperoxide of disodium 3,3 ′-(1,4-naphthalene)bispropionate (NDPO 2), dihydrorhodamine 123, microplate screening assay Introduction infection, ischemia or injury. It is well known that a few mediators play a prominent role in the In biological tissues, inflammatory processes involve inflammatory cascade, namely arachidonic acid- complex physiological responses, resulting from derived lipid compounds ( i.e . eicosanoids) and interactions between cells and soluble factors, to cytokines. On the other hand, several lines of evidence indicate that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a pivotal role in Correspondence to: Eduarda Fernandes PhD, REQUIMTE, Departa- cellular damage often observed in many inflammatory mento de Química-Física, Faculdade de Farmácia, Universidade do 1–3 Porto, Rua Aníbal Cunha, 164 4099-030 Porto, Portugal. conditions. Accordingly, it has been shown that Tel: +35 1 222 078968; Fax: +35 1 222 078961; several synthetic and/or natural antioxidants are E-mail: [email protected] 4 Received 25 October 2007, revised manuscript accepted 19 February 2008 endowed with potent anti-inflammatory activity. © 2008 W. S. Maney and Son Ltd Redox Report 2008 Vol 13 No 4 153 DOI 10.1179/135100008X308876 Costa et al. Singlet oxygen scavenging activity of non-steroidal anti-inflammatory drugs 1 Figure 1 ROS and RNS produced in the event of inflammatory processes, with emphasis to singlet oxygen ( O2). Attraction of neutrophils to inflammatory sites and subsequent activation of NADPH oxidase results in the formation of •– •– superoxide radicals (O 2 ). O 2 is converted to hydrogen peroxide (H 2O2) spontaneously or through catalysis of •– superoxide dismutase (SOD) from ingested microorganisms. The interactions of H 2O2 with O 2 or with trace levels of • transition metals can lead to the formation of hydroxyl radicals (HO ). H 2O2 can react with hypochlorous acid (HOCl), • – 1 nitric oxide ( NO) or peroxynitrite (ONOO ) to yield O2. Myeloperoxidase (MPO), a hydrogen peroxide oxidoreductase that is specifically found in mammalian granulocytic leukocytes, including neutrophils, monocytes, basophils, and eosinophils, produce HOCl from H 2O2 and chloride ions. Besides its well-established reactivity with H 2O2, HOCl also reacts with lipid hydroperoxides (LOOH; generated during interaction of ROS and RNS with cell membranes, and 1 through catalysis by lipoxygenases and cyclooxygenases) to yield O2. LOOH also reacts with transition metals, resulting in the formation of lipid alcoxyl (LO •) and/or lipid peroxyl radicals (LOO •). It is now well established that the α 1 self-reaction of LOO, containing -hydrogen, generates O2. The inducible nitric oxide synthase enzymes (iNOS) also become activated, resulting in the production of continuous near-micromolar amounts of •NO for long periods. – • •– ONOO is formed from the diffusion-controlled reaction between NO and O 2 . Under physiological pH conditions, – • • – – ONOO is in equilibrium with ONOOH, yielding HO , nitrogen dioxide radical ( NO 2) and nitrate (NO 3 ). ONOO can also – – react with carbon dioxide (CO 2) to form the nitrosoperoxycarbonate anion (ONOOCO 2 ). ONOOCO 2 decomposition – •– • •– then leads to the formation of CO 2 and NO 3 , NO 2 and the carbonate radical anion (CO 3 ). Both HO and CO 3 are known to react with hydroperoxides (ROOH) to generate peroxyl radicals (ROO •), which add to those formed during lipid peroxidation. As stated above, termination reactions involving primary or secondary ROO • generates 1 predominantly O2 Furthermore, it has been extensively demonstrated important role in the inflammatory process. 13–18 Figure 1 1 that several non-steroidal anti-inflammatory drugs summarizes the production of ROS, including O2, and (NSAIDs) are effective scavengers of ROS and RNS, 5–12 RNS during inflammatory processes as reported which probably contributes to their final therapeutic elsewhere. 12,18–21 Beyond its possible contribution to tissue 1 activity. In this respect, the most studied reactive species healing during acute inflammation, O2-mediated tissue •– have been the ROS superoxide radical (O 2 ), hydrogen damage in sustained or chronic inflammatory states, • peroxide (H 2O2), hydroxyl radical (HO ), peroxyl radical suggests that a potential effect against this ROS would be (ROO •) and hypochlorous acid (HOCl), and the RNS important for the therapeutic effect of anti-inflammatory nitric oxide ( •NO) and peroxynitrite anion (ONOO –). drugs. Notwithstanding this rationale, the potential 1 1 Nevertheless, another ROS, singlet oxygen ( O2), in scavenging activity of NSAIDs for O2 remains to be addition to its well-known formation during photo- evaluated. The aim of the present study was to evaluate the 1 sensitization processes, has also been shown to have an scavenging activity for O2 by several chemical families 154 Redox Reort 2008 Vol 13 No 4 Costa et al. Singlet oxygen scavenging activity of non-steroidal anti-inflammatory drugs of NSAIDs – the pyrazole derivatives antipyrine, ketorolac and tolmetin, the indolacetic acid derivatives propy phenazone , dipyrone, and amino pyrine, sulindac etodolac, indomethacin, and acemetacin, as well as the and its metabolites sulindac sulfide and sulindac sulfone, arylpropionic acid derivatives indoprofen, naproxen, the oxazole derivative oxaprozin, the pyrrole derivatives ketoprofen, fenoprofen, flurbiprofen, ibuprofen, and Figure 2 Chemical structures of the studied NSAIDs: the pyrazole derivatives antipyrine, propyphenazone, dipyrone, and aminopyrine, sulindac and its metabolites sulindac sulfide and sulindac sulfone, the oxazole derivative oxaprozin, the pyrrole derivatives ketorolac and tolmetin, the indolacetic acid derivatives etodolac, indomethacin, and acemetacin, as well as the arylpropionic acid derivatives indoprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, ibuprofen, and fenbufen Redox Report 2008 Vol 13 No 4 155 Costa et al. Singlet oxygen scavenging activity of non-steroidal anti-inflammatory drugs fenbufen (Fig. 2). For this purpose, a previously developed specially N,N-dimethyl-4-nitrosoaniline, proceeds with 22 1 non-cellular screening system was used, in which O2 was much faster rates than by the direct oxidation through 1 22 generated by thermal dissociation of the water-soluble light-excited dyes or by O2. Reaction mixtures in the endoperoxide of disodium 3,3 ′-(1,4-naphthalene) sample wells contained the following reagents at the bispropionate (NDPO 2) and was detected by monitoring indicated final concentrations (in a final volume of the 1O -induced oxidation of non-fluorescent dihydro - 250 l): DHR (50 M), histidine (10 mM), the tested 2 µ µ rhodamine 123 (DHR) to fluorescent rhodamine 123 NSAIDs at various concentrations (dissolved in 100 (RH). This system allowed a rapid and thorough mM phosphate buffer, pH 7.4, or DMSO) and 1 comparison of O2 scavenging potencies among the NDPO 2 (1 mM). The assays were performed at 37°C. studied NSAIDs. No interference was found for DMSO under these assay conditions. The fluorescence signal was collected Materials and methods after a 30 min incubation period at the emission wavelength 528 nm with excitation at 485 nm. The Materials effects are expressed as the percentage inhibition of 1 All the chemicals and reagents were of analytical the O2-induced
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