What Is the Use of Turmeric Curcumin in Periodontitis?

Periodontitis is a chronic inflammation caused by local factors such as dental plaque. Mechanical treatments such as supragingival scaling and subgingival curettage are often used, but the morphology of the tooth surface or limitations of the instruments sometimes prevent complete removal of the infectious material. Therefore, drug therapy has become one of the most commonly used adjunctive methods for mechanical treatment. Adjuvant drugs can inhibit the activity of pathogenic bacteria, regulate the host inflammatory response, etc., thereby enhancing the effect of mechanical treatment and restoring periodontal health. Common adjuvant drugs include antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) [1]. However, antibiotics can easily lead to the development of drug-resistant strains or dysbiosis, while NSAIDs may increase the risk of persistent bleeding or the occurrence of hematomas. Therefore, there is an urgent need to discover new adjuvant drugs that are both effective and safe.

Natural plant extracts have the advantages of being cost-effective and having few side effects, and have gradually become a research hotspot [2]. Curcumin is an active polyphenol extracted from the plants turmeric and galangal, and has anti-inflammatory, antioxidant, antibacterial and wound-healing effects [3]. Periodontal destruction is caused by direct damage from plaque microorganisms and indirect damage from the excessive immune response they trigger. Therefore, curcumin's antibacterial and anti-inflammatory effects can be used to treat periodontitis. However, low bioavailability limits the complete translation of curcumin's in vitro benefits into clinical applications. Therefore, different drug delivery systems such as liposomes, nanoparticles, solid dispersions, emulsions, micelles, etc. have been developed and applied [4]. This article reviews the mechanism of curcumin in the prevention and treatment of periodontitis and the different delivery strategies of curcumin, with the aim of providing ideas for basic research and clinical applications of curcumin in the prevention and treatment of periodontitis.

I. The pharmacological effects of curcumin on periodontitis

1. Antibacterial effect

Curcumin has a strong antibacterial effect and can exert a bacteriostatic effect through a variety of antibacterial mechanisms, such as affecting the permeability of cell membranes, the expression of bacterial division proteins and virulence factor genes, etc. Bocher et al. [5] constructed an in vitro biofilm model by implanting an artificial periodontal pocket around a titanium rod and introducing various pathogenic bacteria extracted from the patient's gingival sulcus. They found that the total bacterial count treated with curcumin was reduced by 97.35% (P < 0.05), which was significantly stronger than the control group.

Further studies showed that curcumin can inhibit the growth of periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum and Tannerella forsythia. Among them, 20 mg/mL curcumin can inhibit the growth of P. gingivalis biofilm by 80%, and the dose-dependent inhibition of P. gingivalis virulence factors (gingipain R and gingipain K) activity [6]. Moreover, curcumin and its derivatives can be inserted into the phospholipid bilayer to increase membrane permeability, and can also inhibit bacterial division by inhibiting the important protein FtsZ, which supplies energy and drives division during bacterial division. This gives curcumin membrane permeability activity and broad-spectrum antibacterial activity, which can be used in combination with antibiotics to improve antibiotic uptake and increase efficacy [7].

2. Anti-inflammatory effect

Curcumin has active anti-inflammatory activity and can be a natural drug option for host inflammation regulation. Curcumin has been shown at the molecular level to inhibit inflammatory factors such as pro-inflammatory cytokines (interleukin, IL) by regulating signal pathways such as NF-κB [8], Janus kinase (Janus kinase, JAK)/signal transducer and activator of transcription (signal transducer and activator of transcription, STAT), mitogen-activated protein kinases (MAPK) [9], etc., inhibits the inflammatory factors such as pro-inflammatory cytokines (interleukins, ILs) -1β and IL-6 and tumor necrosis factor (tumor necrosis factor, TNF) -α, etc., and exerts an anti-inflammatory effect, inhibiting the progression of periodontitis [10]. The NF-κB pathway is one of the main pathways. When stimulated, NF-κB binds to the promoter region of the target gene through a cascade reaction, promoting the transcriptional expression of inflammatory factors.

Modulating NF-κB signal transduction and IL secretion is the most important functional mechanism of curcumin in regulating inflammatory bodies [8]. Curcumin can upregulate the suppressor of cytokine signaling (SOCS)-1 to reduce the expression of the JAK2/STAT3 signaling pathway, thereby downregulating the expression of inflammatory factors to inhibit inflammation [11]. For example, in colitis, curcumin can alleviate colitis symptoms and inhibit dendritic cells by inducing SOCS1 and SOCS3 to downregulate JAK2, STAT3 and STAT6 [12]. Inhibiting the STAT signaling pathway can reduce the expression and level of inflammatory cytokines, thereby reducing diseases caused by inflammatory responses. In addition, curcumin effectively inhibits the expression of inflammatory cytokines in LPS-induced macrophages by regulating the expression and activity of SOCS-1 and SOCS-3 and p38 MAPK [9]. Moreover, curcumin can significantly reduce inflammatory pain by inhibiting the JNK/MAP signal pathway in nerve cells [13].

Xiao et al. [14] demonstrated in a rat model of periodontitis induced by ligation that curcumin can inhibit NF-κB activation and reduce the production of IL-1β, PGE2, and TNF-α, thereby significantly reducing inflammatory cell infiltration. In addition, Diomede et al. [15] found that in vitro experiments showed that curcumin may act on periodontal stem cells through a novel mechanism of reactive oxygen species (ROS) cascade, namely Toll-like receptor 4/myeloid differentiation factor 88/NF-κB/inflammasome NLRP3/cysteine aspartate protease 1/IL-1β signaling pathway, thus becoming a new target drug for restoring homeostasis within tissues.

3.Osteoprotective effect 

Curcumin has a strong osteoprotective effect, mainly by inhibiting inflammatory bone loss and promoting stem cell proliferation and differentiation. Curcumin reduces the inflammatory response and resorption of the alveolar bone by inhibiting TNF-α, IL-6, and other NF-κB receptor activators (receptor activator of nuclear factor-κB, RANK) and RANK ligand (receptor activator of nuclear factor-κB ligand, RANKL), reducing the inflammatory response and resorption of the alveolar bone [16]. RANKL induces osteoclast differentiation and is the main regulator of bone metabolism and the key to the mechanism of alveolar bone destruction in periodontitis.

In vitro experiments in gingival fibroblasts found that curcumin corrected the decrease in the osteoprotegerin/RANKL ratio induced by LPS, and further testing of periodontitis rats fed curcumin found that alveolar bone loss was reduced and collagen fiber decomposition was weakened [14]. Bakir et al. [10] hypothesized that curcumin inhibits T cell differentiation, thereby reducing osteoclastogenesis. In addition, human periodontal ligament stem cells can differentiate into osteoblasts to promote alveolar bone regeneration. Excessive production of ROS in chronic inflammation disrupts redox homeostasis, leading to cell damage and apoptosis and inhibiting bone differentiation. Studies have found that curcumin pretreatment can protect stem cells from oxidative stress, promote cell proliferation and osteogenic differentiation [17].

II. In vivo pharmacokinetics and safety of curcumin

1. Absorption and distribution of curcumin

The oral absorption rate of curcumin is extremely low and its distribution is limited. The maximum plasma concentration of curcumin in rats after oral administration of 2 g/kg is 1.35 μg/mL, the maximum plasma concentration of curcumin in mice after oral administration of 1 g/kg is 0.22 μg/mL, and the maximum plasma concentration of curcumin in volunteers after oral administration of 12 g is 0.051 μg/mL [18]. This may be due to the fact that curcumin is not water-soluble, is poorly absorbed in the digestive tract, is also subject to first-pass elimination by the liver, and most of the curcumin that enters the lower digestive tract is rapidly metabolized or excreted, resulting in extremely low blood concentrations. Coupled with the fact that curcumin is easily bound to plasma proteins, its distribution in tissues is limited. In mice injected intraperitoneally with 0.1 g/kg curcumin, the content of curcumin in the intestine reached a maximum value (0.117 g/kg), and the content of curcumin in the spleen, liver, kidney and brain was 0.0261 g/kg, 0.0269 g/kg, 0.0075 g/kg and 0.0004 g/kg, respectively [19].

2. Metabolism and excretion of curcumin

Curcumin is metabolized quickly in the body, mainly in the liver and intestines, and excreted in the feces. In mice orally administered with 1 g/kg curcumin, the plasma curcumin concentration decreased rapidly after 1 h and dropped below the detection limit (5 × 10-9 g/mL) within 6 h [19]. Burapan et al. [20] further found in vitro that curcumin was demethylated by the human intestinal bacterium Blautia sp. MRG-PMF1 to demethylcurcumin, and then demethylated to demethylcurcumin. After oral administration, most curcumin is excreted in the feces, and a small amount is absorbed in the intestine and rapidly metabolized in the liver and plasma [18]. After oral administration of 1 g/kg curcumin to rats, about 75% was excreted in the feces, while the amount in the urine was negligible [21].

3.Safety of curcumin

As a substance classified by the FDA as generally recognized as safe [22], curcumin is highly safe. No significant toxic effects were found in rats when they were given curcumin orally up to 5 g/kg, and no teratogenic or carcinogenic effects were found in long-term studies lasting more than three generations, nor was there any damage to reproductive capacity [19]. The first phase of clinical trials showed that curcumin is safe in humans even at high doses (12 g/d), and no significant adverse reactions were found in volunteers [23]; curcumin preparations at a dose of 0.5 g, taken orally twice a day for 30 days, are safe for humans [24].

III. Common delivery systems for curcumin

Different strategies such as increasing curcumin solubility, synthesizing curcumin nanodrugs, combining adjuvants, synthesizing new curcumin derivatives and analogues, and designing curcumin hybrid molecules have all been used to improve the bioavailability of curcumin [25]. Among these strategies, liposomes, nanoparticles, adjuvants, micelles, and hydrogels are the most widely used. Table 1 shows the commonly used delivery systems for curcumin and a comparison of the characteristics of different delivery systems.

1. Liposomes

Liposomes are artificially constructed spherical bilayer vesicles [26]. Encapsulation in liposomes can significantly improve the physicochemical properties of curcumin. Curcumin liposomes coated with bovine serum albumin were constructed as a long-circulating drug delivery system, which has the characteristics of low phagocytosis, sustained release, enhanced stability, and non-toxicity [27]. In addition, the development of targeted liposomal formulations can further improve the efficacy of curcumin. Barattin [28] and others prepared a new type of pH-sensitive liposome, modified with tetraarginine-distearoylglycerol and its pegylated counterpart, which contains a pH-sensitive polyanionic block. In the acidic environment of tumors, the arginine moiety is easily exposed, enhancing the targeted binding of liposomes to cancer cells.

2. Nanoparticles

Nanoparticle drug delivery systems can improve the solubility of hydrophobic drugs. At the same time, the small particles can prolong the retention time of the drug in the body circulation and change the distribution, and allow targeted and trans-barrier transport [29]. Curcumin was encapsulated in solid lipid nanoparticles using an emulsification cryogelation method to increase intracellular curcumin concentrations and its accumulation in mitochondria, as well as improve its aqueous solution stability, in order to enhance the therapeutic activity of curcumin [30]. Twelve volunteers orally administered a γ-cyclodextrin curcumin preparation and curcumin, respectively. Compared with direct oral administration of curcumin, the γ-cyclodextrin curcumin preparation resulted in higher plasma curcumin concentrations, enhanced curcumin absorption, and significantly improved bioavailability [31]. Currently, common nanoparticles also include mesoporous silica nanoparticles and protein-based nanocarriers [32], which can also be used in the future to improve the bioavailability of curcumin.

3. Adjuvants

Adjuvants can alter the metabolism of curcumin and thus indirectly improve its bioavailability, such as piperine, lecithin and sesamin. In vivo metabolism involves the transfer of glucuronic acid groups to the hydroxyl groups of curcumin to form glucuronides, which are less active and are excreted more easily. Piperine is an inhibitor of glucuronic acid acidification in the liver and intestines [33]. It mainly improves the bioavailability of curcumin by inhibiting the aldehyde oxidation of curcumin by glucuronosyltransferase. Curcumin and piperine were given to rats with an artificially constructed periodontitis model. It was found that compared with the curcumin group alone, the combined application significantly reduced the activity of NF-κB in periodontal tissues, reduced the infiltration of inflammatory cells, increased collagen content, and had the potential to promote periodontitis soft tissue healing and bone tissue mineralization [34]. Further in vitro experiments found that curcumin in combination with piperine can inhibit the expression of osteoclast-specific markers tartrate-resistant acid phosphatase (TRAP), cathepsin K and calcitonin receptor, reduce osteoclastogenesis, and have no toxic effect on periodontal ligament cells [35].

4. Micelles

Micelles refer to ordered aggregates of molecules formed by surfactants in aqueous solutions, consisting of a hydrophilic shell and a hydrophobic core, which can load hydrophobic drugs. Nanometer-scale micelles can spill over from the blood vessel wall into cells, and the hydrophilic shell of the micelle can escape removal by the reticuloendothelial system, prolonging the circulation time of the drug. Curcumin polylactic-polyglycolic acid nanomicelles were prepared, and their antibacterial activity against Pseudomonas aeruginosa was investigated. It was found that compared with free curcumin, curcumin micelles can better penetrate biofilms and effectively destroy them, enhancing the antibacterial effect of curcumin [36]. Lee D et al. [37] designed an acid-responsive curcumin polymer conjugated by 1,4,4'-trimethylenedipiperidine and polyethylene glycol acrylate. After incorporating curcumin into its hydrophobic backbone, it self-assembles into micelles under aqueous conditions due to its amphiphilicity, and rapidly releases curcumin under acidic conditions. The problem of poor water solubility of curcumin is solved, and it has the ability to stimulate pathological reactions, achieving controlled release.

5. Hydrogel

A hydrogel is a semi-solid gel with water as the dispersing medium. It usually has a hydrophilic three-dimensional network structure, which can achieve the advantages of slow-release curcumin, strong mucosal affinity, and long local retention time. It is suitable for use as a transdermal or mucosal drug delivery system. Hydroxypropyl-β-cyclodextrin was used to improve the solubility of curcumin, which was loaded into a bacterial cellulose hydrogel. It significantly inhibited staphylococcus, and also had blood compatibility, cell compatibility and antioxidant properties [38]. Poloxamer F 127 was used as a temperature-sensitive polymer, and Popul P 934 was used as a pH-sensitive polymer to a controlled-release curcumin hydrogel was formulated. In vitro experiments showed that the gel was easy to insert into periodontal pockets and controlled the release of drugs for a long time. Further clinical trials found that after scaling and root planing in patients with periodontitis, the application of the gel significantly reduced the periodontal probing depth and bleeding index compared with no gel, and improved patient compliance [39].

IV. Clinical application of curcumin

In clinical studies, the use of curcumin as an adjunct to periodontal treatment can significantly reduce periodontal inflammation. Ravishankar et al. [45] selected periodontitis patients and applied curcumin gel and ornidazole gel respectively. At the one-month evaluation, curcumin gel had a better therapeutic effect than ornidazole gel, and the depth of periodontal pockets, plaque index and clinical attachment loss were significantly reduced. Pulikkotil et al. [46] selected healthy subjects and applied curcumin, chlorhexidine and chlorhexidine-metronidazole gel as the only method of maintaining oral hygiene to construct a 29-day gingivitis model, periodontal status and changes in IL-1β and mucosal-associated epithelial chemokine (MEC/C-C motif chemokine 28, CCL28) in gingival crevicular fluid were evaluated. It was found that the periodontal status in the curcumin group was comparable to that in the chlorhexidine-metronidazole gel group, but IL-1β and CCL28 were significantly lower than those in the chlorhexidine gel group.

In addition, a meta-analysis of nine randomized controlled trials involving 420 participants/sites [47] showed that curcumin had a similar effect on reducing the depth of periodontal pockets, clinical attachment loss, gingival index and plaque index as chlorhexidine, which was also used as an adjuvant drug. Another meta-analysis evaluating the effect of curcumin mouthwash on plaque and gingival index also reached similar conclusions, with curcumin and chlorhexidine having comparable efficacy in reducing plaque (CI: -0.53, 1.07, P=0.51) and gingival index (CI: -0.35, 0.09, P=0.24) [48]. Chlorhexidine is currently the “gold standard” drug for adjuvant periodontal medication. Curcumin is comparable to it in efficacy, which indicates that curcumin plays an important role in inhibiting periodontal pathogenic bacteria, reducing the degree of inflammation, and improving periodontal clinical indicators.

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