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Emerging Concepts on the Anti-Inflammatory Actions of Carbon Monoxide-Releasing Molecules (CO-Rms)

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Emerging Concepts on the Anti-Inflammatory Actions of Carbon Monoxide-Releasing Molecules (CO-Rms) Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs). Roberto Motterlini, Benjamin Haas, Roberta Foresti To cite this version: Roberto Motterlini, Benjamin Haas, Roberta Foresti. Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs).. Medical Gas Research, BioMed Central, 2012, 2 (1), pp.28. 10.1186/2045-9912-2-28. inserm-00769904 HAL Id: inserm-00769904 https://www.hal.inserm.fr/inserm-00769904 Submitted on 3 Jan 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Motterlini et al. Medical Gas Research 2012, 2:28 http://www.medicalgasresearch.com/content/2/1/28 MEDICAL GAS RESEARCH REVIEW Open Access Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs) Roberto Motterlini*, Benjamin Haas and Roberta Foresti* Abstract Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo compounds capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. CO-RMs containing transition metal carbonyls were initially implemented to mimic the function of heme oxygenase-1 (HMOX1), a stress inducible defensive protein that degrades heme to CO and biliverdin leading to anti-oxidant and anti-inflammatory actions. Ten years after their discovery, the research on the chemistry and biological activities of CO-RMs has greatly intensified indicating that their potential use as CO delivering agents for the treatment of several pathological conditions is feasible. Although CO-RMs are a class of compounds that structurally diverge from traditional organic-like pharmaceuticals, their behaviour in the biological environments is progressively being elucidated revealing interesting features of metal-carbonyl chemistry towards cellular targets. Specifically, the presence of carbonyl groups bound to transition metals such as ruthenium, iron or manganese appears to make CO-RMs unique in their ability to transfer CO intracellularly and amplify the mechanisms of signal transduction mediated by CO. In addition to their well-established vasodilatory activities and protective effects against organ ischemic damage, CO-RMs are emerging for their striking anti-inflammatory properties which may be the result of the multiple activities of metal carbonyls in the control of redox signaling, oxidative stress and cellular respiration. Here, we review evidence on the pharmacological effects of CO-RMs in models of acute and chronic inflammation elaborating on some emerging concepts that may help to explain the chemical reactivity and mechanism(s) of action of this distinctive class of compounds in biological systems. Keywords: Inflammation, Carbon monoxide-releasing molecules (CO-RMs), Oxidative stress, Inflammatory mediators, Bactericidal activities Introduction upon up-regulation of HMOX1 and this has been The heme oxygenase enzymes (HMOX1 and HMOX2) demonstrated in some studies that directly measured generate, among other interesting molecules, the gas CO production ex-vivo [3,4]. Research conducted in the carbon monoxide (CO) [1]. The quantity of the gas pro- past years has progressively elucidated the role of duced over time depends on the tissue examined, as HMOX1 in mammalian systems. The protein was recog- HO-2 is constitutively expressed in the endothelium, tes- nized early on as an important component of the stress tes and brain while HMOX1 is highly inducible in all tis- response [5,6] but it was only when detailed exploration sues by many kinds of stressful stimuli [2]. In addition, of the function of its products was performed that an in- the availability of the substrate heme, which is cleaved dispensable action for HMOX1 as an anti-oxidant and by heme oxygenases in the α position to release CO, will anti-inflammatory system emerged [7,8]. CO appears to strictly determine how much CO can be produced in the contribute most significantly to these anti-inflammatory cell. However, it is expected that CO levels will increase activities by regulating a variety of transcription factors, inflammatory proteins and pathways [9-11]. This role * Correspondence: [email protected]; [email protected] is consistent across many inflammatory conditions, INSERM U955, Equipe 3, Faculty of Medicine, University Paris-Est Creteil, Creteil, France © 2012 Motterlini et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Motterlini et al. Medical Gas Research 2012, 2:28 Page 2 of 12 http://www.medicalgasresearch.com/content/2/1/28 although the specific pathways affected might differ from ruthenium, iron or manganese as metal center, and bora- one disease to another. nocarbonates are the two major classes of CO-RMs in Exposure of cells, tissues and animals to sub-toxic our portfolio [15,16,59,61]. Our own investigations and amounts of CO gas has been used successfully to repro- studies with collaborators revealed that metal carbonyls duce the anti-inflammatory properties of HMOX1 and are better anti-inflammatory agents than boranocarbo- has helped to unravel many of the mechanisms under- nates but the reasons for this difference are unknown at lying this effect [10,11]. The use of CO gas as a thera- present. The chemistry and pharmacological pro peutic agent is also underscored by clinical trials perties of these compounds is becoming a topic of currently ongoing in patients who will receive CO by in- great interest since in the last 2-3 years other research halation for the treatment of pulmonary arterial hyper- groups have synthesized a variety of different new tension, post-operative ileus and idiopathic pulmonary CO-RMs. Recently ruthenium imidazole oxime car fibrosis (see www.clinicaltrials.gov). In parallel and as an bonyls [62], photoactive and nanoCO-RMs [63,64], alternative to this experimental approach, we have fo- enzyme-triggered CO-RMs [65], CO-RMs encapsulated cused our strategy on utilizing chemicals that could bind in micelles [66] and rhenium-based CO-RMs [67] have and carry CO stably but deliver the gas when used in been developed. However, for most of these new mole- biological systems. We have identified and termed these cules a detailed picture of their behaviour in cells, tis- compounds CO-releasing molecules (CO-RMs) [12-14] sues and in vivo models of disease is not yet available, and have extensively studied their biochemical, bio- and will be required to evaluate their full pharmaco- logical and pharmacological effects in many in vitro and logical potential. In this context it is important to in vivo models of disease [9,15-17]. The chemical struc- emphasize that, once CO is liberated, the potential tox- ture of the best characterized CO-RMs (CORM-2, icity of the residual molecule containing the transition CORM-3, CORM-A1 and CORM-376) is represented in metal needs to be carefully evaluated. To date a sys- Figure 1 (see also chemical formula in List of Abbrevia- tematic in vivo toxicological profile of CO-RMs has not tions). Thanks to strong collaborations with chemists, yet been performed but this will be required once a we have generated CO-RMs with improved water solu- lead compound will be identified for a given patho- bility, diverse chemical structures, various rates of CO logical indication. release and stability [9,15,58-60]. The results have been In this article we will review the role of CO-RMs in encouraging as the concentrations and doses of CO- protection against inflammatory conditions, focusing RMs used in all studies were such that the final CO primarily on their effect on oxidative stress and nitric exposure was below the threshold believed to cause tox- oxide (NO) production, two of the main initiators of the icity. In addition, as shown in Table 1, the data obtained inflammatory cascade. The biochemical and physio- so far support promising pharmacological actions of logical assays used to determine CO liberation or trans- CO-RMs that could be useful to counteract inflamma- fer of CO to cellular targets and their interesting tory conditions. Metal carbonyl complexes, containing anti-bacterial actions will also be discussed. CO CO Cl H OC Cl CO OC N Ru Ru Ru OC Cl CO OC Cl CO O Cl O CORM-2 CORM-3 + 2- 2 Na O H O CO Me OC S Mn N H BC Me OC S Me O H CO O Me CORM-A1 CORM-371 Figure 1 Chemical structure of the best characterized CO-RMs which have been shown to exert anti-inflammatory and anti-bacterial activities in vitro and in vivo (see also Table 1 for more details). Motterlini et al. Medical Gas Research 2012, 2:28 Page 3 of 12 http://www.medicalgasresearch.com/content/2/1/28 Table 1 Effect of CO-RMs on in vitro and in vivo inflammatory disease models Type of CO-RM Inflammatory disease models Effect on inflammatory markers/ References in vitro and in vivo Overall
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