2088 Current Medicinal Chemistry, 2012, 19, 2088-2103 Anti-Inflammatory Agents from Plants: Progress and Potential M.C. Recio*, I. Andújar and J.L. Ríos Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Spain Abstract: The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases. Keywords: Boswellic acid, clinical trials, cucurbitacins, inflammatory bowel disease, phenolics medicinal plant therapy, natural products, rheumatoid arthritis. 1. INTRODUCTION The four classic hallmarks of inflammation are redness, heat, swelling, and pain. Inflammation is the body’s natural response to harmful stimuli and is achieved by the movement of plasma and leukocytes from the blood into injured tissues. This particular type of immune response is important for the body to ward off harmful pathogens and is classified as acute inflammation [1]. During inflammation leukocytes accumulate and amplify the response. In normal circumstances, the immune system has several mechanisms to resolve the inflammatory responses. The resolution of inflammation requires the termination of pro-inflammatory signalling pathways and clearance of inflammatory cells, allowing the restoration of normal tissue function. A failure of these mechanisms may lead to chronic inflammation and disease. During the inflammatory process, different cell types are recruited, including monocytes that locally differentiate into macrophages. This leads to the regulated production of various pro- and anti- inflammatory mediators including cytokines, such as tumor necrosis factor ((TNF)-α and interleukins (IL)-1β and IL-6, chemokines, and inducible enzymes such as cyclooxygenase (COX)-2, all of which play critical roles in controlling the inflammatory process. For its part, Nuclear Factor (NF)-κB regulate genes involved in many aspects the inflammatory response [2]. In response to a diverse pro-inflammatory stimuli, cytokines and oxidative stress, induce pro-inflammatory genes including cytokines, chemokines and adhesion molecules which are essential for both the innate and adaptative immune response. Current treatments for the chronic inflammation involved in diseases such as arthritis, autoimmune disorders, cancer, dementia, diabetes, neurodegeneration, and vascular diseases are not definitive because of potential adverse events and a lack of efficacy. Whitehouse [3] has recently reviewed and considered the problem of the serious concomitant side effects of powerful anti- inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The use of anti-inflammatory steroids has limitations particularly with high dosage and prolonged use (Table 1). Lanas [4] has reviewed the adverse effects of non-selective non-steroidal anti-inflammatory drugs (NSAID) and COX-2 selective inhibitors in the upper and lower gastrointestinaltract, and the need for a measurement that incorporates both upper and lower GI complications as an endpoint in outcome studies with NSAID.These drugs are associated with acute renal failure [5]. COX-2 inhibitors (COXIBS) are differentiated pharmacologically *Address correspondence to this author at the Département de Farmacologia, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100-Burjassot, Valencia, Spain; Tel: +34963543283; Fax: +34963544943; E-mail: maria.c.recio@uv.es from traditional NSAIDs by inhibiting only the COX-2 enzyme, and clinically by lower rates of upper and lower gastrointestinal harm. All of these drugs (NSAID, and COXIB) may also be associated with increased risk of cardiovascular harm [6]. Recently, the safety and immunogenicity of biological therapy have been reviewed by Van Assche et al., [7]. The safety profile in randomized controlled studies of all biological agents in Crohn's disease (CD) and ulcerative colitis (UC) has been generally favorable, but a small percentage of patients experience severe side effects on biological therapy, including pneumonia, tuberculosis, lymphoma, demyelination, drug-induced lupus, or hepatotoxicity. The authors conclude that the balance of risk and benefit must be judged for individual patients. Table 1. Limitations to Anti-Inflammatory Steroids 1 Suppressing steroid biogenesis in the adrenal cortex 2 Early onset side effects: Hyperglycemia and diabetic complications. Aggravation of ulcers. Diminished resistance to infections. In juveniles, (reversible) reduction of growth 3 Slower developing side effects, sometimes irreversible: Osteoporosis, joint destruction, skin atrophy, Impaired wound healing, Excessive hair growth, fat redistribution, Accelerating atherosclerosis, hypertension In this context, the identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Although their application is often viewed with skepticism by the Western medical establishment, medicinal extracts used in ancient medical traditions such as Ayurveda on the Indian subcontinent and traditional Chinese medicine are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise [8].Plants may also be an important source of biologically active natural products and could be considered a promising avenue for the discovery of new drugs due to easy access and relatively low cost [9]. Aspirin (Fig. 1), a cornerstone for the treatment of inflammation-associated diseases, was derived from the salicylic acid found in the bark of the willow tree (Spiraea ulmaria, Salix species), which has traditionally been used to treat fever and inflammation in many cultures worldwide for at least four millennia. Agents derived from plants include anti-inflammatory flavonoids, terpenes, quinones, catechins, alkaloids, etc., all of which are known to modulate the expression of pro-inflammatory signals. Indeed, many plant-based preparations are reported to - /12 $58.00+.00 © 2012 Bentham Science Publishers