Licorice as a herbal extract in periodontal therapy

Introduction

Periodontal disease is caused by specific pathogens which results in inflammation of the tooth-supporting structures and subsequently causes the continued breakdown of alveolar bone and periodontal ligament. The pathogenesis of periodontal diseases involves two major causative factors. The first is the microbial factor, that is, the presence of increased levels of periodontopathogenic bacteria in subgingival tissues, which causes periodontal destruction by producing proteinases and toxins (1,2). The pathogens associated with periodontitis are Porphyromonas gingivalis, Treponema denticola, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia. The other factor is the immune response of the host to the periodontal pathogens, which is the over-production of mediators of inflammation such as cytokines, prostaglandins, and matrix metalloproteinases (MMPs), which regulate the continuance of periodontal disease (3).

Periodontal therapy primarily includes scaling and root planing to eliminate the local factors, that is, plaque and calculus, and to maintain satisfactory oral hygiene. Since periodontal disease is known to be an inflammatory condition with a microbial etiology, the adjunctive use of locally applied or systemic administration of antimicrobials and/or host response‐modulating medications has been suggested.

Conventional synthetic agents such as chlorhexidine products which are used therapeutically and prophylactically in dentistry have some disadvantages such as altered taste sensation, tooth staining, and resistance to bacteria, which limit their usage over a long term (4). Therefore, innovative strategies need to be developed against periodontal diseases, such as exploring the extensively available medicinal plants. The active ingredients in medicinal plants restore health, with maximum efficiency and minimal side effects. Herbal extracts incorporated into medications have been found to be safe and efficacious for the treatment of several oral health conditions such as gingival bleeding, dental caries, halitosis, and mouth ulcers. The extracts obtained from aloe vera, green tea plant, neem, tulsi, propolis, rosemary, meswak, turmeric, chamomile, tea tree oil, peppermint oil, cranberry, clove, ginger, etc. have been used commonly for the prevention and treatment of different oral diseases. Herbal extracts contain phytochemicals that are responsible for the desired anti-inflammatory and antimicrobial effects (5). Herbal formulations are gaining widespread attention as they do not contain artificial preservatives, alcohol, colors, or flavors, which are commonly found in other drugstore products.

One such herb with medicinal properties is licorice (Glycyrrhiza glabra). Licorice, synonym being sweet wood, is found in the Mediterranean region and in a few regions of Asia. Licorice is a perennial herb that holds a sweet taste and has widespread pharmacological effects on human beings. Licorice extract is derived from the dried, unpeeled stolons and roots of Glycyrrhiza uralensis and G. glabra.

However, limited information is available on the use of this herb in periodontal therapy. The mechanism of action by which licorice works against periodontal diseases has not been elucidated in previous studies. The aim of this review was to enumerate the bioactive compounds present in herbal licorice extract and to elucidate the beneficial effects of licorice and its derivatives in periodontal therapy.

Methodology

The literature search was performed using three databases which included PubMed, Google Scholar, and Cochrane, in addition to searching reference lists of original and review articles. The combination of the following keywords was used to search for relevant articles: “licorice,” “Glycyrrhiza glabra,” “periodontal therapy,” and “periodontal disease.” Relevant studies published between 1985 and 2022 were selected. Only articles in English language were considered, and unpublished data were not sought. Two reviewers obtained information on the quality and characteristics of the included studies.

Components in licorice extract

Licorice is a potential source of natural anti-inflammatory agents. Its major active component is glycyrrhetinic acid (GA) that is derived from licorice root extract. Major phytochemicals found in licorice are shown in Table I (Fig. 1) (6).

Safe usage of licorice

The Food and Drug Administration (FDA) has labeled licorice as “Generally Recognized as Safe.” It has been suggested to be safe when used in minimal quantities by people who are not allergic to glycyrrhizin (7,8). Intake of excessive quantity, that is, over 200 mg, of licorice may cause hypertension, hypokalemia, rhabdomyolysis, respiratory impairment, muscle paralysis, hyperparathyroidism, acute renal failure, and encephalopathy (9). According to the World Health Organization (WHO), 100 mg/day of licorice can be used safely without adverse effects. A potential risk of excessive bleeding may be seen in patients using medications for anti-clotting for cerebrovascular or cardiovascular diseases in conjunction with licorice-containing herbal medications due to its antiplatelet and anticoagulant effects (10).

Effects of licorice

Licorice constituents have shown antimicrobial (11), antiviral (12), anti-inflammatory (13), antidiabetic, antitumor, immunoregulatory (14), sedative (15), antidepressive (16), estrogenic (17,18), antioxidant (19), hepatoprotective (20), neuroprotective activities (21), and skin effects (22). The active constituents of licorice extract have a potential role on the oral microorganisms as well as the host response involved in orodental diseases like periodontitis, dental caries, recurrent aphthous ulcers, and candidiasis.

Antiviral effects – Licorice extracts inhibit the growth of viruses such as herpes simplex, influenza virus, and vesicular stomatitis virus. Glycyrrhizin prevents the replication of viruses and interferes with viral binding (12).

Antidiabetic activity – Glycycoumarin, glycerin, etc., present in G. glabra extracts lower blood glucose level by binding to peroxisome proliferator-activated receptor (PPAR) gamma. Glabridin helps in efficient glucose utilization and prevents glucose intolerance by translocation of GLUT-4 (14).

Antitumor activity – 18-β-GA and glycyrrhizic acids induce mitochondrial permeability transition causing tumor cell apoptosis (14).

Immunoregulatory effect – Glycyrrhiza extracts stimulate the immune system by production of macrophages and lymphocytes, and increasing the phagocytic capacity of neutrophils. It prevented the accumulation of immune complexes involved in autoimmune diseases such as systemic lupus erythematosus (14).

Sedative effect – Glabridin shows sedative and hypotonic effects by positively modulating the gamma-aminobutyric acid (GABA) receptors (15).

Antidepressive effect – Licorice shows antidepressive effects by inhibition of monoamine oxidase and increasing epinephrine and dopamine levels in the brain (16).

Estrogenic effect – Licorice extracts show estrogenic activity through uterine retention and vaginal opening. Isoflavones present in licorice can influence sexual development, impair estrus cycling, and alter the proper functioning of the ovarian, hypothalamus, and pituitary glands. Glabridin can be used as a treatment for menopausal symptoms (17,18).

Hepatoprotective activities – Glycyrrhizin has shown improved liver histology and reduced serum aminotransferases. It shows hepatoprotective effect against CCl4-induced oxidative stress, prevents oxidative and hepatic damage caused due to aflatoxin, and improves liver function (20).

Neuroprotective activities – Licorice has an antioxidant activity that can reduce brain damage by eliminating or utilizing the free radicals and improving neural function and memory (21).

Skin effects – Licorice is popular in treating dermatitis, pruritus, cysts, and eczema. It is also used for cosmetic formulation as a depigmenting agent to inhibit the tyrosinase enzyme (22).

Mechanism of action

The beneficial effects of licorice can be due to various mechanisms.

Licorice in periodontal disease

The bioactive ingredients in licorice like glycyrrhizin, glabridin, licorisoflavan A, licochalcone A, and licoricidin are effective against periodontal disease. Table II summarizes the studies which suggest the potential use of licorice in periodontal therapy.

These ingredients exhibit antimicrobial, anti-inflammatory, and anti-adherence effects (Fig. 2). Since the etiology of periodontal diseases is complex involving the periodontal pathogens and host immune response, dual functionality compounds such as the phytochemicals in licorice offer therapeutic superiority. Phytochemicals are structurally distinct from the conventional microbial-derived antibiotics, and so are advantageous as antimicrobials. The phytochemicals act against different bacterial strains by inhibiting the efflux pumps, inhibiting the cell wall biosynthesis by interacting with the cell membrane, and by inhibition of enzymes such as dihydrofolate reductase, urease, and sortase A (51). Thus, their mechanisms of action are different from classic substances and against which microbial resistance does not develop.

The ability of licorice to inhibit the formation of dental plaque enhances its significance in the treatment of periodontal disease. At high concentrations of licorice extract (5%-10%), there was a slight reduction in bacterial growth and formation of plaque was completely inhibited. No effect was seen on either adherence or growth with lower concentrations. At high concentrations (0.5%-1%) of its pure active component, that is, glycyrrhizin, there was a complete inhibition in the adherence, whereas partial inhibition was observed at lower concentrations. The surface activity of glycyrrhizin could be responsible for its inhibitory effect, as bacterial adherence and growth are known to be affected by surfactants. Bacterial adherence can also be inhibited by the adsorption of glycyrrhizin onto smooth surfaces. Licorice extract shows minimal antibacterial activity along with its effect on inhibition of plaque. Glycyrrhizin as a vehicle can be effective for topical agents used orally due to its sweetness, good dispersing properties, and the ability to remain stable in the form of aqueous gels. This suggests that the balance of the oral microbial flora will not be affected on using glycyrrhizin as an oral medication (52).

Phytochemicals of G. glabra reduce bacterial growth and inhibit the mediators of inflammation at the infection site. It also inhibits the activity of osteoclasts responsible for destruction of alveolar bone in periodontal disease and promotes the formation of bone by stimulating osteoblastogenesis. High amounts of inflammatory markers like interleukin (IL)-1β, IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-α, and RANKL are present in patients with periodontal disease. Licorice extract showed potent anti-inflammatory properties by inhibiting these proinflammatory mediators stimulated by lipopolysaccharide (LPS) from A. actinomycetemcomitans and P. gingivalis (32).

Resorption of alveolar bone is an important feature of periodontitis. The differentiation, activation, and survival of osteoclasts are regulated by RANKL leading to bone resorption. Glabridin can be used to inhibit osteoclastogenesis by preventing the activation of signaling molecules induced by RANKL and subsequent transcription factors for osteoclast precursors, suggesting its therapeutic potential (34).

Recommendations for future research

Though the use of herbals for medicinal purpose is traced back to several centuries, it is only in recent evidence-based era that methodical and systematic approaches to study their properties have been reinstituted. This has sparked a wide interest for their application in all healthcare specialties including periodontal therapy. The beneficial phytochemicals in licorice must be studied so as to incorporate these herbal extracts in oral care products that may be useful in dental therapy.

In vitro studies have shown the capability of licorice and its bioactive components in periodontal therapy; however, most of the clinical studies have limitations pertaining to the design of the study and the number of participants included in the study, which makes them statistically insignificant. Thus, further clinical studies need to be carried out to investigate the oral care products containing licorice extracts, in the forms of toothpaste, mouthwash chewing gum, and gel to be able to validate its beneficial effects. The local application of these bioactive compounds would be more suitable. For example, the local application of a licorice-based gel into sites with periodontal disease permits the bioactive ingredients to be released slowly, which will act locally on the periodontal pathogens and the host immune response, the two contributory factors in the destruction of periodontal tissues.

Further research focusing on the in vivo anti-inflammatory/antimicrobial effects of licorice is required on larger sample sizes to better understand its specific role in the management of periodontitis. Clinical trials evaluating the effect of licorice extract on periodontopathogens and inflammatory cytokines would be recommended.

Conclusion

The usage of herbal agents for the treatment of periodontal disease is considered as an intriguing alternative to conventional antibiotics due to their lesser negative effects and to overcome drug resistance during treatment. Licorice extracts exhibit a wide range of biological effects such as anti-inflammatory, antioxidant, and antimicrobial activities. It has the ability to prevent the release of proinflammatory mediators and MMPs from host cells, and hence it is a potent agent for periodontal therapy. The bioactive ingredients present in this herb help in reducing loss of alveolar bone, which is commonly associated with periodontal disease. It should also be emphasized that no adverse effects have been seen with the use of licorice extracts. Hence, local application of licorice-containing agents into the diseased periodontal sites can be beneficial, which would act locally on periodontopathogens and the host inflammatory response.

Disclosures

Conflict of interest: The authors declare no conflict of interest. Financial support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.