Abstract
Botanical remedies have been used for centuries to treat various inflammatory conditions. Recent research has elucidated many mechanisms of action for such herbs, including modulation of cytokines, downregulation of NF-kB, and the inhibition of cyclooxygenase enzymes. It has also indentified active constituents and led the way to developments for enhancing the bioavailability and efficacy of these natural anti-inflammatory agents. This review describes some recent advances in our understanding of the actions and efficacy of 2 ancient anti-inflammatory herbs—turmeric (Curcuma longa) and frankincense (Boswellia serrata)—with modern examples of the evidence of their efficacy in osteoarthritis.
Introduction
Inflammatory conditions are common in clinical practice. Acute inflammation is a part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Thus, inflammation is required for the healing of wounds and infection.
In acute inflammation, a cascade of biochemical events propagates the inflammatory response, involving the local vascular system, immune system, and various cells within the injured tissue. Chronic inflammation leads to a progressive shift in the type of cells present at the site of inflammation and is uniquely characterized by a simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation must therefore be controlled to ameliorate symptoms and prevent chronic inflammatory disease.
Numerous inflammatory mediators have been identified as being critical in regulation of the inflammation response. The nuclear factor NF-kB is considered as to be a nearly archetypal pro-inflammatory pathway, because NF-kB is so decisive in its control of the expression of genes that lead to upregulation of cytokines (a proinflammatory event). NF-kB, unsurprisingly, is chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, among others.1, 2
This resolution of inflammation is driven by dual-acting mediators known as lipoxins, resolvins, and protectins. In addition to serving as agonists to stop and lower neutrophil infiltration to inflamed tissues, pro-resolution molecules promote the uptake and clearance by macrophages of cells undergoing apoptosis, as well as of microbial pathogens. These actions at sites of inflammation stimulate antimicrobial activities in the mucosal epithelial cells.3
Endogenous pro-resolution molecules are not immunosuppressors but instead activate numerous mechanisms promoting homeostasis. The multifactorial activity of these pro-resolution molecules in stimulating and accelerating resolution validates, in some respects, the use of natural agents over pharmaceuticals in promoting resolution of inflammation, since pharmaceuticals tend to target single enzymes and pathways, whereas natural agents tend to operate on multiple pathways simultaneously, such as:
- Cessation of neutrophil and eosinophil tissue infiltration
- Stimulation of non-phlogistic recruitment of monocytes (ie, without the elaboration of pro-inflammatory mediators)
- Activation of macrophages to phagocytize microorganisms and apoptotic cells
- Increased lymphatic removal of phagocytes
- Stimulation of expression of antimicrobial defense mechanisms
Botanicals as Anti-Inflammatories
Herbal medicines have been used for centuries to treat inflammatory conditions. Much of the current research is focused on the identification, isolation, and characterization of active principles from crude extracts of known medicinal plants. Examples from the medical research community abound. Baicalin, a flavone isolated from the Chinese herb Scutellaria baicalensis Georgi and used in China to treat infectious diseases, inhibits T-cell proliferation and production of interleukin 1β, interleukin 6, tumor necrosis factor (TNF)-α, interferon-γ, monocyte chemotactic protein 1, and macrophage inflammatory protein (MIP)-1α.4,5 Berberine, a major isoquinoline alkaloid found in Mahonia, Hydrastis, Coptis, and other herbs, inhibits interleukin (IL)-1β, IL-6 and TNF-α.6,7 Bilberry juice modulates plasma concentration of NF-kB-related inflammatory markers in subjects at increased risk of cardiovascular disease.8
While it is important to understand the active agents within medicinal plants, it should also be with caution that we extract and use constituents in isolation.
However, exclusive focus on individual biochemical targets neglects the fact that strong synergy of multiple constituents in a crude drug may prove more potent and effective than any single purified compound, or that interactions of co-occurring phytochemicals may help nullify the toxic effects of individual constituents. So while it is important to understand the active agents within medicinal plants, it should also be with caution that we extract and use constituents in isolation. This article will review two anti-inflammatory herbs—turmeric and frankincense—from the perspective of their traditional use as well as modern applications.
Turmeric (Curcuma longa)
The dried, ground rhizome of the perennial herb Curcuma longa has been used in Asian medicine since the second millennium BC. This perennial plant in the ginger family (Zingiberaceae) is cultivated throughout the tropics and is used as both a spice and a medicine. A traditional aromatic, stimulant, and colorant, turmeric has also been used topically to treat wounds, inflammation, and tumors.9 Turmeric as the whole herb as well as some of its constituents has been found to exert antioxidant, anti-inflammatory, and anti-mutagenic activity.10 It's approved in Europe for indigestion and mild biliary complaints but is contraindicated in bile passage obstruction.11
Curcumin is a term that is sometimes used to refer to any or all of the curcuminoid compounds in turmeric. There are 3 main curcuminoids in turmeric, of which curcumin (diferuloylmethane) is the best studied. Other curcuminoids in turmeric include demethoxycurcumin and bisdemethoxycurcumin. Curcumin imparts yellow color to the plant and is a powerful anti-inflammatory agent. Many mechanisms of anti-inflammatory activity have been identified for curcumin. For example, curcumin downregulates COX-2 and iNOS enzymes, likely by suppressing NF-kB activation;12 it inhibits arachidonic acid metabolism via lipoxygenase and scavenging of free radicals generated in this pathway; it inhibits the production of inflammatory cytokines, TNF-α , IL-1, IL-2, IL-6, IL-8, IL-12, monocyte chemoattractant protein (MCP), and migration inhibitory protein; it downregulates mitogen-activated, Janus kinases, and protein kinase C.13, 14, 15 In addition, the vanilloid part of the curcumin molecule is important for activation of the transient receptor potential vanilloid 1 (TRPV1), which plays an important role in nociception. Among the several modes of action identified for turmeric, experimental research indicates that curcumin blocks TRPV1 activation and thereby inhibits TRPV1-mediated pain hypersensitivity.16 Curcumin has also demonstrated antioxidant, hepatoprotective, antimutagenic, anticarcinogenic, antitumor, antibacterial, fungistatic, and vulnerary properties.17
After curcuminoids, the key phytochemicals are turmeric terpenes, including various turmerones, borneol, cineole, eugenol, and curcumone. These are found in the turmeric essential oil,and are antifungal, antibacterial, antiparasitic, choleretic, analgesic, hepatoprotective, and anti-inflammatory.18 The plant also contains various sugars, proteins, and resins.
Curcumin and Cancer
There is a considerable amount of research devoted to the overlap between inflammation and cancer. Curcumin's anticancer effects are exerted upon numerous biochemical pathways involved in carcinogenesis, cell proliferation, apoptosis, metastasis, and angiogenesis. It suppresses growth of several tumor cell lines: Inhibition of constitutive NF-kB activation by curcumin can in turn inhibit proliferation of prostate cancer, multiple myeloma, mantel cell lymphoma, bladder cancer, melanoma, pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), ovarian cancer, glioblastoma, and lung cancer.14 Overexpression of cell cycle regulatory proteins is considered a hallmark of cancer. Curcumin modulates these in numerous ways. It suppresses activation of transcription factors implicated in carcinogenesis, including NF-kB, activator protein 1 (AP-1), and others. It modulates early growth response protein 1 (erg-1), peroxisome proliferation-associated receptor gamma (PPAR-γ), β-catenin, and Nrf-2). It downregulates Bcl-2, BclXL, inflammatory enzymes (eg, COX-2), MMP-9, TNF, protein kinases, and adhesion molecules. It induces caspases, impairs Wnt signaling events, inhibits cell-cell adhesion, and blocks transition of the cell cycle from G2 to M. It also inhibits high levels of inflammatory chemokines and other metastasis-stimulating events, as well as events that promote angiogenesis. Curcumin also increases chemosensitivity of cancer cells to anticancer drugs and to radiation, while protecting healthy cells from radiation's effects.19
As a result of these, and many other potential anticancer activities, curcumin has demonstrated promise for several types of cancers, including breast, colorectal, gastrointestinal, genitourinary, lung, leukemia, lymphoma, melanoma, ovarian, pancreatic, prostate, and sarcoma.20, 21, 22, 23, 24, 25
Bioavailability of Curcumin
The clinical utility of curcumin has been limited by its chemical instability at intestinal pH values,26 by its low water solubility, and by its poor oral bioavailability and quick conjugation and excretion. These properties lead to less than ideal conditions for therapeutic utility. The consequence is that several human studies of non-complexed curcumin have failed, even at high doses,27 and its full clinical potential remains unrealized.28,29,30
In humans, curcuminoids are very poorly absorbed, rapidly metabolized, and quickly eliminated. Once in the plasma, however, curcumin is quite stable and even permeable to hard-to-reach tissues, like the brain. The challenge, therefore, has been to find a way to stabilize curcuminoids in the gut and deliver them to the plasma without the use of synthetic agents or substances that are otherwise undesirable. Complexing curcumin to phosphatidylcholine (PC) into a "phytosome" is one recently successful method a overcoming this issue.31
Preliminary pharmacokinetics (PK) research in animals demonstrated significant bioavailability advantages of turmeric-PC phytosome over non-complexed powdered curcuminoids.32 In a follow-up PK study in humans, bioavailability of total curcuminoids as evaluated by the plasma area under the curve (AUC) was about 29-fold higher for those taking the phytosome than in subjects taking conventional turmeric extract (95% curcumin). Specifically, the bioavailability was enhanced 18-fold for curcumin, 54-fold for bis-demethoxycurcumin, and 62-fold for demethoxycurcumin.33
Clinical efficacy of curcumin phytosome in osteoarthritis
Curcumin and curcumin-PC phytosome have demonstrated anti-inflammatory properties in humans and in experimental animal models. In addition, the phytosome has demonstrated clinical efficacy in painful, albeit less inflammatory, conditions such as osteoarthritis. The efficacy and safety of a proprietary curcumin-PC complex (Meriva®, Indena S.p.A ) were investigated in an 8-month, randomized, double-blind, placebo-controlled clinical trial.34 One hundred patients with osteoarthritis were given two 500 mg tablets daily, 1 after breakfast and 1 after dinner, providing a total of 200 mg curcumin/day. Clinical endpoints were WOMAC score, Karnofsky Performance Scale Index, and treadmill walking performance. The researchers also evaluated a series of inflammatory markers including IL-1β, IL-6, soluble CD40 ligand (sCD40L), soluble vascular cell adhesion molecule (sVCAM)-1, erythrocyte sedimentation rate (ESR). The curcumin-PC phytosome significantly improved the Karnofsky Scale (from 73.3 at inclusion to 92.2 at the completion of the study), with no significant improvements in the control group. Scores for pain dropped significantly (P<0.05) following curcumin phytosome administration from 16.6 to 7.3, with no significant effects in the control group. Other improvements were also noted (eg, on stiffness, treadmill test). Moreover, the curcumin-PC phytosome induced statistically significant reductions of all markers of inflammation studied, while the control group had only marginal and non-significant effects on all parameters.
Frankincense (Boswellia serrata)
Frankincense is a resinous extract from the trees of the genus Boswellia, which are native to India and the Arabian peninsula. It has been used since antiquity in religious ceremonies and for perfume production, and its medicinal properties have been recognized and prized for millennia.35 In modern times, the pharmacological characteristics and clinical efficacy of Boswellia serrata have been studied, with research published and systematically reviewed in the medical literature.36
The main active constituents of boswellia are the boswellic acids, most importantly acetyl-11-keto-beta-boswellic acid (AKBA). AKBA has demonstrated many significant immunomodulatory and inflammation-modulating effects in preclinical research. The best-documented action of boswellic acids is probably the inhibition of the inflammatory mediator 5-lipoxygenase.37 However, other factors such as cytokines (interleukins and TNF-α) and the complement system are likely molecular targets.38,39 AKBA also naturally inhibits NF-kappaB.40
Clinical efficacy of boswellia in inflammatory disease
A systematic review of data from randomized clinical trials showed boswellia extracts are clinically effective in asthma, rheumatoid arthritis, Crohn's disease, osteoarthritis, and collagenous colitis.38 However, of the 47 potentially relevant studies considered, only 7 met all inclusion criteria. No serious safety issues were noted. The authors found the totality of the evidence encouraging, but not compelling, mainly due to the prevalence of methodological flaws in many studies. The heterogeneity of materials studied should also be considered. Modern extracts of boswellia are standardized to AKBA content. The most effective extracts to date employ as standardization level of 30% AKBA.
In a randomized, double-blind, placebo-controlled clinical trial of a 30% AKBA boswellia extract (5-LOXIN), researchers found that the extract significantly reduced pain and improved physical functioning in OA patients.41 Seventy-five participants received either 100 mg or 250 mg (delivering 33 mg or 75 mg AKBA, respectively) per day of boswellia extract for 90 days. Each patient was evaluated for pain and physical function using the visual analog scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index at baseline and at days 7, 30, 60 and 90. The cartilage degrading enzyme matrix metalloproteinase-3 was also evaluated in synovial fluid from OA patients. Measurement was also made of several other biochemical parameters in serum and hematological parameters, and urine analyses were performed to evaluate safety of the extract. At the end of the study, both doses of boswellia extract conferred clinically and statistically significant improvements in pain scores and physical function scores in the OA patients. Significant improvements in pain score and functional ability were recorded in the treatment group supplemented with 250 mg as early as 7 days after the start of treatment. The authors also reported a significant reduction in synovial fluid MMP-3 in the treatment group. A later clinical study comparing 2 different extracts of boswellia produced similar results.42
Conclusion
Turmeric and frankincense are two herbs with ancient medicinal usage undergoing intense scrutiny and study for their modern applications and mechanisms of action. Many of the actions of key actives within these plants have been identified and described. Unlike most drugs, however, even single actives in these plants (eg, curcumin) work via multiple mechanisms, rather than targeting a single enzyme or receptor.
The slower onset of symptom relief produced by these and other botanical agents (as compared to pharmaceutical anti-inflammatory agents) should not be dismissed as lower efficacy. Rather, it is indicative of the gradual restoration of homeostasis. When time and symptom management permit, this outcome has advantages over the isolated suppression of specific inflammatory mechanisms and mediators, with fewer adverse effects and more sustained and sustainable clinical results.
