Role of Curcumin in Inflammatory Disorder: Arthritis, IBD and Psoriasis

1.1 Inflammation and its aftermath

Inflammation is a complex defensive response to damaging stimuli such as infection or injury with tissue repair. [2] It is the immune cells and signalling pathways that are on alert to eliminate the threats and return to balance. This procedure is usually classified as acute and chronic types. Acute inflammation is a rapid and short-lived process marked by signs of redness, swelling and pain. [19] Once the stimulation ends, the body usually reverts to normal. In contrast, chronic inflammation is an enduring and pathologic state of immune activation. Failure to resolve leads to slow tissue damage and organ failure.[19]

Chronic inflammation is involved in many disorders such as IBD, arthritis, cardiovascular diseases, diabetes and cancer. [2,38] This chronic disease is associated with the overproduction of reactive oxygen species (ROS) and pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. These mediators form a vicious cycle that can greatly accelerate the progression of disease over time. [2,19]

In the last decades, the world burden of chronic inflammatory diseases has dramatically increased, affecting millions of people. This trend is a great burden on healthcare systems and world productivity, not to mention the physical cost. Ultimately, the chronic dysregulation of these immunological signals wreaks havoc on the overall quality of life for patients across the world. [38]

1.2 Need for Safer Anti-Inflammatory Drugs

Currently available anti-inflammatory therapies mainly include corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents and biologics. While these therapies are effective in controlling inflammation and alleviating symptoms, their long-term use is generally associated with serious side effects such as gastrointestinal toxicity, cardiovascular complications, immunosuppression, hepatotoxicity, renal dysfunction and increased susceptibility to infections. [2,13] Moreover, some patients show poor therapeutic response or develop resistance to the conventional therapies, limiting their clinical efficacy. [38]

1.3 Curcumin Introduction

Curcumin is a polyphenol found in the rhizome of the Curcuma longa spices plant widely used in traditional remedy to treat pain and inflammation. [1,9] Its possible therapeutic benefits have raised a great deal of scientific interest in recent decades because of its properties as an anti-inflammatory, antioxidant and anticancer agent. [1,13]

Curcumin's anti-inflammatory properties can be attributed to its ability to modulate several molecular targets (NF-κB, MAPKs, COX-2, and iNOS) and its ability to scavenge free radicals for the antioxidant capacity of the body. Curcumin exhibits low toxicity and a great deal of potential for treating arthritis and inflammatory bowel disease. Some of its disadvantages for clinical use, however, include low aqueous solubility, low bioavailability, and rapid metabolism. [1,2,13,28] These issues have led to the investigation of several new formulations to improve the therapeutic efficacy of curcumin, including nanoparticles, liposomes, and micelles. As such, curcumin shows great promise as a natural treatment for inflammatory diseases. [9,19]

2. Curcumin: Source and Chemical Profile

2.1 Source and Origin

The significant bioactive compound found in turmeric (the perennial herbaceous plant known as Curcuma longa) is called curcumin; this plant belongs to the Zingiberaceae family (ginger). It grows best in tropical/subtropical climates, with most of the world's turmeric production taking place in Asia (India and Southeast Asia being the most substantial producing regions). The dried and powdered rhizomes (roots) of the Curcuma longa plant are the therapeutic/cooking parts of the plant.[7,9] Turmeric has been utilized for centuries to treat numerous inflammatory diseases, pain (including but not limited to chronic arthritis and menstrual cramps), skin disorders, gastrointestinal disorders (diarrhea/constipation), and liver disorders as an integral treatment for multiple systems of traditional medicine (i.e., Ayurvedic, Traditional Chinese, and herbal medicine).[13] The health-promoting effects of turmeric can be attributed to its curcuminoid content. Curcuminoids are a sub-group of compounds that contain high levels of antioxidant activity; curcumin is the most prolific and only curcuminoid contained at 3%-5% (w/w) in turmeric. Additionally, turmeric contains three primary curcuminoids that have been classified based on their structural variations (curcumin, demethoxycurcumin, and bisdemethoxycurcumin); the greatest number of pharmacological activities (i.e., anti-inflammatory, antioxidant, anti-microbial, anti-cancer, and immunomodulatory) are associated with curcumin.[7,19] Curcumin (diferuloylmethane) is therefore recognised as a very promising drug for the treatment of numerous chronic inflammatory conditions. Curcumin also has increased in use by the medical industry as an anti-inflammatory and preventative substance. [9,38]

2.2 Chemical Structure

3.2 Chemical Structure Curcumin is an organic compound from nature and has the formula C21H20O6 (or C21H20O6) The molecular weight of cCurcumin is about 368.37 g/mol, and C21H20O6 is a pale orange solid with a crystal-like consistence. The structure of cCurcumin is composed of two symmetrical aromatic o-methoxy phenolic rings joined by a chain of seven carbon atoms that includes an α, β-unsaturated diketone moiety. Curcumin contains several different functional groups: (1) two phenolic hydroxyl groups; (2) two methoxy groups; (3) β-diketone moiety; and (4) conjugated double bonds. These functional groups account for most of curcumin's antioxidant and anti-inflammatory activity. The two phenolic hydroxyl functional groups exhibit free-radical scavenging properties, while the diketone moiety can chelate with metal ions and create interactions with different molecular targets throughout the body. There are three major bioactive compounds that are classified as curcuminoids: (1) curcumin; (2) demethoxycurcumin; and (3) bisdemethoxycurcumin. The primary structural differences between curcumin and the other curcuminoids lie within the number of methoxy functional groups found at each end of the phenolic rings. [19]

2.3 Physicochemical Properties

Curcumin, a polyphenolic compound found in turmeric root, has been used for many centuries in traditional medicine to provide relief of pain associated with injury, illness or trauma. [1,13] In recent time, curcumin has been the subject of numerous contemporary studies investigating its various pharmacological properties and whether or not it exhibits antioxidant, anti-inflammatory and anticancer properties. [1,9] Further research has shown that curcumin acts as an anti-inflammatory agent through various pathways that involve different molecular targets such as NF-kB, MAPKs, COX2 and iNOS, as well as enhancing the body’s antioxidant status through the elimination of free radicals. [2,19,38] Despite showing low or no toxicity and having some demonstrated efficacy in the treatment of various inflammatory conditions such as arthritis and inflammatory bowel disease, the clinical use of curcumin continues to be limited due to its low solubility in water, poor absorption following administration to mammals, and rapid metabolism following administration. [1,2,13,28] Several new technologies such as nanoparticles, liposomes and micelles have been developed to improve the delivery and effectiveness of curcumin for the treatment of inflammatory conditions. This use of curcumin for the long-term treatment of inflammation appears to be a very exciting potential new area of study. [19,9]

3. Pathophysiology of Inflammation

Inflammation is a protective response of the immune system to noxious stimuli, such as infections, toxins, tissue injury and oxidative stress. Its main role is to remove harmful agents, repair damaged tissues and restore normal body function. But, ongoing or uncontrolled inflammation is linked to chronic diseases such as arthritis, inflammatory bowel disease (IBD), psoriasis, cardiovascular diseases, diabetes, and cancer. [19,38]

The inflammatory process includes activation of immune cells (macrophages, neutrophils, dendritic cells and lymphocytes) that release inflammatory mediators, cytokines and enzymes that increase the inflammatory response. [19]

3.1 Role of Cytokines in the Inflammatory Process

Cytokines are important when it comes to regulating immunity and inflammation. Examples of pro-inflammatory cytokines include tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). All three of these cytokines have been associated with chronic inflammatory diseases. [17,19] TNF-α is produced by activated macrophages and monocytes and is responsible for leukocyte recruitment, fever induction, and oxidative stress generation through NF-κB pathway activation. IL-1β is another important proinflammatory cytokine produced by macrophages and monocytes in response to infection or tissue injury. This cytokine helps to activate many inflammatory genes and has been shown to enhance vascular permeability and activate leukocytes via its effects on NF-κB and MAPK pathways by opposing the pro-inflammatory effects of TNF-α. In addition to mediating the inflammatory response, IL-1β is also responsible for the tissue damage associated with various inflammatory diseases (such as rheumatoid arthritis, psoriasis, and IBD) and increasing levels of IL-1β have been correlated with several inflammatory conditions including rheumatoid arthritis, psoriasis, and neuroinflammatory disorders. [17,19,39]

3.2 The NF-κB Pathway

The NF-κB signalling pathway is an important regulator of inflammation and immune responses. NF-κB controls the expression of inflammatory cytokines, chemokines, COX-2 and iNOS.[17].

Normally, NF-κB is sequestered in the cytoplasm by binding to inhibitory proteins (IκBs). NF-κB is released after degradation of IκB as a result of IκB kinase (IKK) activation by inflammatory stimuli including cytokines, ROS and bacterial toxins. Once activated, NF-κB travels to the nucleus to start transcription of inflammatory genes.Permanent activation of NF-κB causes a surge in the levels of TNF-α, IL-1β and IL-6, which contribute to chronic inflammation and damage to body tissue. [17,19]

3.3 Oxidative Stress and Inflammation

Oxidative stress occurs when the body's ability to produce reactive oxygen species (ROS) through normal metabolism exceeds the body's ability to defend itself from oxidative stress through its antioxidant defence system. Some well-known ROS that are produced by the immune system throughout the body are superoxide anion (O2-*), hydrogen peroxide (H2O2), hydroxyl radical (•OH) (27). Activated immune cells can produce a large amount of ROS in response to an inflammatory response and these ROS can damage DNA, protein, and lipid molecules as well as cellular membranes. In addition, oxidative stress is an important mediator of the activation of inflammatory signalling pathways such as NF-kB, MAPK, and JAK/STAT, which leads to the production of more cytokines, mediated through oxidative stress, to cause more inflammation (17,39).The continuous production of ROS and the continuous eliciting of the release of inflammatory mediators leads to a vicious cycle that results in chronic inflammation, cellular injury, fibrosis, and progression of disease. As such, targeting cytokines, oxidative stress, and NF-kB signalling provide opportunities for new therapies in the treatment of patients with inflammatory diseases (17,19,38).

4. Mechanism of Action of Curcumin in Inflammation

Curcumin is widely regarded as an effective anti-inflammatory compound due to its ability to modulate numerous molecular targets, inflammatory mediators, and signal transduction pathways involved in the inflammatory response. Courcumin's effectiveness in treating chronic inflammation is attributable to its ability to act on multiple molecular targets, unlike classical anti-inflammatory medications, which typically act on only one target. [19,40] Most of the anti-inflammatory effects of curcumin can be attributed to its ability to inhibit the NF-κB pathway, decrease the production of pro-inflammatory cytokines, decrease reactive oxygen species (ROS) levels, and inhibit the activity of anti-inflammatory enzymes such as COX-2 and iNOS. [2,19]

4.1 Suppression of NF-κB Signaling Pathway

Curcumin has been shown to inhibit the NF-κB Pathway, which is a critical molecular pathway controlling inflammatory response and chronic damage due to inflammation. Chronic activation of NF-κB is linked to disease states such as arthritis, inflammatory bowel disease, diabetes and cancer. [19,40] The mechanism of action of curcumin is by inhibiting every step of NF-kB activation; for example, inflammatory signals stimulate the activity of IκB Kinase (IKK), leading to the degradation of IκB proteins. Once IκB has been degraded, NF-κB is free to translocate into the nucleus and to activate transcription of the NF-κB regulated genes that cause the production of inflammatory signals. Therefore, by inhibiting IKK and stabilizing IκB curcumin maintains NF-κB in its unactivated form and confines it to the cytoplasm. In addition to inhibiting the phosphorylation of NF-κB subunits, including p65, curcumin also restricts the nuclear translocation of these proteins and inhibits their transcriptional activity. As a result of these actions, curcumin inhibits the release of inflammatory mediators (TNF-α, chemokines, adhesion molecules, COX-2, iNOS) that contribute to tissue injury and inflammatory response. [19]

4.2 Inhibition of COX-2 and Inflammation Enzymes

Curcumin inhibits enzymes of inflammation, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), which are involved in the production of prostaglandins and nitric oxide during inflammation. These enzymes cause pain, swelling and tissue injury when they are overexpressed. [39]

Curcumin inhibits activity of COX-2 & iNOS and diminishes inflammatory pain and oxidative injury. Curcumin also inhibits other inflammatory enzymes, such as lipoxygenase (LOX), phospholipase A2 and xanthine oxidase, thereby reducing inflammatory mediator generation. [19,27,39]

4.3 Decrease in Reactive Oxygen Species (ROS)

Chronic inflammation and damage to tissue have been linked to reactive oxygen species (ROS) as significant contributors. When there is an inflammatory response activated, neutrophils and macrophages produce large amounts of ROS that activate more inflammatory pathways. [39] Curcumin can stop the production of ROS through several different means such as by scavenging directly for the free radicals, inhibiting the activity of NADPH oxidase, regulating oxidative stress in the mitochondria, and promoting antioxidant enzymes. It also prevents lipid peroxidation, which helps keep cells and their membranes safe from oxidative stress. [40] By inhibiting cytokines via the lowering of ROS levels, and subsequently inhibiting cytokines and inflammation, as a result, curcumin inhibits the activation of NF-κB and MAPK signalling pathways. [19,40]

5. Role of Curcumin in Specific Inflammatory Disorders

Curcumin has been demonstrated to play an important role in treating or preventing many diseases associated with inflammation due to its ability to reduce inflammation and inhibit the production of proinflammatory cytokines, for example.

Studies have shown that curcumin reverses the production of proinflammatory cytokines and/or cell types responsible for inflammation, and therefore has demonstrated success in treating/relieving symptoms of many chronic inflammatory illnesses such as:

• Osteoarthritis
• Rheumatoid Arthritis
• Psoriasis
• Inflammatory Bowel Disease (IBD)

5.1 Curcumin's Effectiveness on Arthritis

Arthritis is an inflammatory disease of the joints and surrounding tissues resulting in pain, swelling, stiffness, restricted motion and continuous destruction of the joints. The two main types of arthritis are rheumatoid arthritis (RA) and osteoarthritis (OA), where RA, an autoimmune disease, is characterized by synovial inflammation and destruction of cartilage, and OA is characterized by deterioration of cartilage and low-grade chronic inflammation. [5,17]

The inflammatory cytokines TNF-α, IL-1β, and IL-6 contribute to arthritis through their ability to activate NF-κB and MAPK pathways which are directly implicated in cartilage breakdown and increase in oxidative stress and bone destruction. [5]

Mechanism of Curcumin in Arthritis

Multiple pathways exist for the mechanism by which curcumin reduces arthritis symptoms. It has been shown that curcumin can have effects on nuclear factor kappa B (NF-κB) and downregulate the activity of several pro-inflammatory substances such as tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase (COX)-2, prostaglandins, and nitric oxide synthase (iNOS). [13,14]

In osteoarthritis (OA), studies have proved that curcumin can:

• Protect chondrocytes from apoptosis
• Promote collagen synthesis
• Decrease cartilage degradation
• Inhibit Matrix Metalloproteinases (MMPs)
• Increase joint mobility/function [5]

 

Fig1: Curcumin's Immunomodulatory and Anti-Inflammatory Mechanisms in Arthritis

 

Fig:2 Mechanistic Overview of Curcumin in the Management of Psoriasis

 

Fig:3 Immunomodulatory Mechanisms of Curcumin in IBD, Crohn’s Disease and Ulcerative Colitis

9. Limitations and Future Perspectives

Although the therapeutic promise of curcumin in inflammatory disorders is evident, numerous limitations hinder its widespread clinical use. The main challenges are poor bioavailability, rapid metabolism, variability in formulations, lack of standardization and limited large scale clinical evidence. [9,13]

9.1 Need for Further Clinical Trials

Most of the evidence for efficacy of curcumin has come from in vitro studies, animal experiments and small-scale clinical trials. While positive effects have been observed in diseases such as arthritis, psoriasis and inflammatory bowel disease, many studies use:

• Not enough samples
• Short-duration treatment
• Heterogeneity of the patient population
• Different formulas and dose regimens [19]

These variations hamper a direct comparison between studies and preclude the development of standardized therapeutic guidelines. [13]

Thus, large multicenter clinical trials with long-term follow-up are required to:

• Confirm therapeutic effect
• Determine optimal dosing regimens
• Assess long-term safety
• Develop pharmacokinetic profiles
• Evaluate clinical outcomes in different populations [9]

Further studies are also needed to assess the use of curcumin as an independently or adjunctively with conventional anti-inflammatory drugs.

10. CONCLUSION

The naturally occurring chemical curcumin is the main active substance in turmeric (*Curcuma longa*). It is found to be effective in treating many long-lasting inflammatory diseases such as arthritis, psoriasis, and inflammatory bowel disease (IBD). Some of its mechanisms of action include its anti-inflammatory and antioxidant properties, which include blocking the activation of the NF-κB signaling pathway and reducing the levels of other pro-inflammatory chemicals, such as TNF-α, IL-1β, and IL-6, and reducing oxidative stress. Clinical and experimental data show that curcumin decreases inflammation, improves symptoms associated with inflammatory diseases, protects the body from oxidative damage, and enhances patients' quality of life, with relatively little risk of toxicity.Recent developments in the delivery of curcumin, including new methods to improve the solubility of curcumin in water and the utilization of glycosides and phospholipids to maximize delivery, have led to improvements in the effectiveness of curcumin in the body. Nevertheless, factors limiting the widespread clinical use of curcumin, such lack as its low solubility in water, rapid metabolism, and of consensus on standardized clinical treatment guidelines for the use of curcumin, will require further clinical research studies with enough participating patients to answer major questions about the optimal doses and long-term safety of curcumin and the best ways to create standardized curcumin products. Overall, curcumin appears to be a safe, multi-targeted, and effective treatment for the management of inflammatory diseases, and it has a great deal of promise for the future of clinical use.

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