Terpenes from Natural Products with Potential AntiInflammatory Activity Terpenes from Natural Products with Potential Anti-Inflammatory Activity

Additional information available at the end of the chapter Abstract The development and progression of many diseases is related with an inflammatory process, which could affect different organs or tissues. Currently, many drugs are used to treat inflammation. However, some of these compounds induce severe side effects. For this reason, the search of new therapeutic options for the treatment of inflammation is very desirable. Medicinal plants have been an interesting source for obtaining new active compounds, including several terpenes and terpenoids with anti-inflammatory activity. This book chapter includes 62 sesquiterpenes, 34 diterpenes, and 22 triterpenes with anti- inflammatory activity. The anti-inflammatory effect was evaluated using in vitro , in vivo , and both models. These terpenes were obtained from 44 plant species belonging to 25 botanical families. Eight of theses species belong to the Asteraceae family and four to Lamiaceae family, respectively, and the other species belong to 13 different botanical families, one sesquiterpene was obtained from a sponge and two diterpenes were isolated from corals.


Inflammation
Inflammation is a response of vascularized tissues to infections and tissue damage, and contributes to the beginning and progression of diseases such as Alzheimer, type 2 diabetes, obesity, stroke, and cancer [1,2]. The symptomatology of inflammation is characterized by pain, redness, swelling, heat, and loss of function. Depending on the time of duration, inflammation might be categorized into acute and chronic. Acute inflammation is considered as a protective response and occurs within minutes, hours, or few days after exposure to infections and/or tissue damage. Acute inflammation is characterized by the exudation of fluid (edema), elevated blood flow, and migration of neutrophils [3]. Chronic inflammation occurs when the initial response fails to repair tissue damaged or when a n o x i o u ss t i m u l u si sp e r s i s t e n t ,a n di sc h a r a c t e r ized with more tissue destruction, fibrosis, long presence of lymphocytes [4]. Macrophages, dendritic cells, and mast cells initiate the inflammatory process secreting pro-inflammatory cytokines such as interleukin 6 (IL-6) and interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), and inducing the production of reactive oxygen species (ROS), which play an important role in the modulation of inflammation [5]. The long-term use of current drugs for the treatment of inflammation, including nonsteroidal anti-inflammatory drugs (NSAIDs), the disease-modifying anti-rheumatic drugs (DMARDs), and steroids display several undesirable side effects such as gastric ulcers, nephrotoxicity, and hepatotoxicity, among others [6]. The search of new anti-inflammatory agents with less side effects is highly desirable. Furthermore, the efficient treatment of inflammation may be an interesting and effective way to prevent chronic diseases like cancer.

Terpenes
Natural products are a good source of anti-inflammatory compounds [7]. Terpenes, containing a C5 isoprene unit, are the large group of natural compounds found mostly in higher plants, but also in lower invertebrates. There are approximately more than 50,000 terpenes that have been isolated from different plant species. Terpenes, composed of isoprene units (C 5 H 8 ), play a variety of vital roles in plant species, including growth and development and defense against herbivores and environmental stress [8]. Terpenes possess a great variety of biological activities as antimicrobial, against cancer, malaria, and anti-inflammatory effects in acute and chronic inflammatory conditions like chronic obstructive pulmonary disease and osteoarthritis [9,10].
Cyperus rotundus, a perennial plant, has several pharmacological activities, including antibacterial [11], antimutagenic [12], and anti-inflammatory [13]. Isocyperol, a sesquiterpene isolated from the rhizomes of C. rotundus, inhibited the production of NO and PGE2, decreased the levels pro-inflammatory interleukins (IL-1β and IL-6) and the monocyte chemotactic protein-1 (MCP-1), and suppressed the gene expression of iNOS and COX-2 in RAW-264 murine macrophages stimulated with lipopolysaccharide (LPS). In addition, isocyperol reduced the serum levels of NO, PGE2, and IL-6 in LPS-induced septic shock in mice, via suppression of the NF-кB and STAT3 signaling pathways [14]. Dodonaea viscosa induces gastroprotective [15], antibacterial [16], analgesic, and anti-inflammatory activities [17,18]. Hawtriwaic acid, an ent-clerodane diterpene, was isolated from D. viscosa and showed antiinflammatory activity on the murine ear edema induced with 12-O-tetradecanoylphorbol-13acetate (TPA) by one or multiple applications. In both models, the compound diminished the edema [19]. Hawtriwaic acid at doses of 5, 10, and 20 mg/kg decreased knee inflammation in a murine model of monoarthritis induced with kaolin/carrageenan, by the reduction of serum levels of the pro-inflammatory interleukins Il-1β, IL-6, and TNF-α, and the increase in the serum levels of the anti-inflammatory interleukin IL-10 [20]. Ursolic acid, a pentacyclic triterpene found in many plant species, was identified for the first time in 1920 in the epicuticular waxes of apples. Ursolic acid exerts cytotoxic effects in various cancer cells by the inhibition of the STAT3 signaling pathway [21] and the induction of apoptosis [22]. Ursolic acid has protective effects on lung, kidney, liver, and brain, exerts anabolic effects on skeletal muscle [23], and induces antinociceptive activity in abdominal constriction test induced by acetic acid and the formalin test in mice [24]. Ursolic acid decreased the paw edema induced with carrageenan in rats [25], decreased the ear edema induced with Croton oil in mice [26], reduced the levels of iNOS, COX-2, IL-1β, IL-6, and TNF-α, and increased the level of IL-10 in macrophages stimulated with LPS [27].
The sesquiterpenes, vernomelitensin and onopordopicrin, isolated from Onopordum illyricum a n dt h et r i t e r p e n e ,S o o t e p i nF ,o b t a i n e df r o mGardenia sootepensis, decreased each NF-κB activity with IC 50 values of 3.6, 8.6, and 20.3 μM, respectively [28,29].
The pro-inflammatory enzymes: (1) inducible the nitric oxide synthase (iNOS), which is involved in the nitric oxide (NO) production, and the cyclooxygenase-2 (COX-2) involved in the prostaglandin production, are estimated in LPS-induced macrophages to evaluate the in vitro anti-inflammatory activity. IL-1 and TNF-α stimulate the production of NO. The inhibitory concentration 50 (IC 50 ) for these two pro-inflammatory enzymes has only been reported in some studies. The sesquiterpenes hydroxycostunolide (IC 50 =0 . 6 8μM), costunolide (IC 50 0.3 μM), and artemorin (IC 50 =0 . 1 6μM), obtained from Inula montana, showed similar or higher potency in the inhibition of NO, compared to that reported for the positive control dexamethasone (IC 50 =0 . 4 5 -4.33 μM) [30]. Further studies are recommended to be performed with theses sesquiterpenes. Toxicological studies to guarantee their safety in long-term studies are also necessary. The in vivo studies evaluate swelling, redness, and pain mainly in rodents.
In the table is show the structure of 62 sesquiterpenes, 34 diterpenes, and 22 triterpenes with anti-inflammatory activity, isolated from 44 plant species, 1 sponge, and 2 corals.

Scientific name Terpene
Structure Anti-inflammatory assay Results Ref. Sesquiterpenes The compounds 1 and 2, tested at a concentration of 80 μM, each, inhibited the NO production by 37.5 and 46.0%, respectively. [31] Nardostachys chinensis Batal.
The compound tested at 30 μM inhibited the protein expression of iNOS and COX-2. [32]

Terpenes and Terpenoids
Scientific name Terpene Structure Anti-inflammatory assay Results Ref.
Acanthoic acid LPS-stimulated RAW 264.7 peritoneal macrophages. Ear edema in mice induced by TPA.

Hispanone
Inhibition of superoxide anion generation and elastase release.
The compounds decreased the NO production with IC 50 values of 10.79 μM and 12.73 μM, respectively. . The compound tested at 25 μg/ml inhibited the production of pro-inflammatory cytokines IL-2, IL-4, IL-6, and IL-17A. The compound decreased the NO production with IC 50 value of 70 μM. [56] Cunninghamia konishii Hayata.

Terpenes and Terpenoids
Scientific name Terpene Structure Anti-inflammatory assay Results Ref.

Erythroivorensin
The carrageenan paw edema model in chicken.
The compound (300 mg/kg orally) showed antiinflammatory effect with similar activity compared to diclofenac (100 mg/Kg).
Salvinorin A Calcium ionophore-stimulated peritoneal macrophages, and in carrageenan-induced pleurisy in rats.
Inhibited the production of leukotrienes. In carrageenaninduced pleurisy in rats, Salvinorin A significantly inhibited LTB 4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung. [63] Casearia sylvestris Sw.
At doses 10 and 100 mg/kg showed a significant reduction of the carrageenan-induced paw edema in rats compared to indomethacin. [64] Terpenes and Terpenoids [29] Protium paniculatum Engl.

Conclusion
This book chapter indicates that there has been an increase in the search of terpenes with antiinflammatory activity in recent years. This fact indicates that terpenes are a topic of interest. The possible mechanisms involved in the anti-inflammatory effects of the terpenes are pointing out on the inhibition of NF-κB, TNF-α, PGE2, and pro-inflammatory cytokines such as IL-6. NF-κB is one of the current targets for the development of new anti-inflammatory drugs [71]. In addition, the molecular targets of terpenes are highly desirable to find target-specific antiinflammatory drugs. The mechanism of action of many terpenes remains to be studied. The combination of terpenes with high anti-inflammatory activity and with studied mechanism of action and currently used drugs could be another strategy for further anti-inflammatory therapy.