Punica granatum: A review on its potential role in treating periodontal disease.

A wide variety of plants possess enormous treasure of medicinal value. Majority of these medicinal plants have been used to treat various systemic conditions successfully. Over the recent years, use of these medicinal plants has resurfaced to treat oral conditions. Among the oral conditions, periodontal disease remains one of the most common. Alternative and preventive options has become the need of the hour in order to overcome the adverse effects of the antimicrobial agents used in large as an adjunct to mainstream periodontal treatment. Punica granatum (Pomegranate) is one of the oldest edible fruit which has a long history as a medicinal fruit. This review is an attempt to highlight the potential of Punica granatum as a preventive and therapeutic aid to periodontal disease.

INTRODUCTION

Gingivitis is inflammation of the gingiva. It is defined as the inflammation of the gingiva in which the junctional epithelium remains attached to the tooth at the original level.[1] Plaque is a requirement for the development of gingivitis.[2] Periodontitis is a complex disease in which disease expression involves intricate interactions of the biofilm with the host inflammatory response and subsequent alterations in bone and connective tissue metabolism.[3] Loss of connective tissue attachment to the teeth is the clinical feature which differentiates periodontitis from gingivitis.[2]

Plaque control is the primary preventive measure to prevent the onset of gingivitis and arrest its progression into periodontitis.[1] Although mechanical plaque control methods are efficient in maintaining adequate levels of oral hygiene, studies have shown that patient compliance in following these methods are not adequate in a large population.[1] In order to overcome the shortcomings of mechanical plaque control methods, various chemotherapeutic agents have been employed and developed to improve the efficacy of daily oral hygiene.[1] Chemotherapeutic agents including systemic antibiotics, antiseptic mouthwashes, local drug delivery of antiseptics and antibiotics, host modulating agents have been used as an adjunct to the conventional periodontal therapy.[14] The search for newer and safer adjunctive therapeutic agents is still ongoing.

Herbs are nature's gift to humans. They have various bioactive components which possess enormous medicinal value with least side effects.[5] Synthetic antimicrobial agents and antibiotics are known to cause antimicrobial resistance, emergence of previously uncommon infections probably due to the inappropriate or widespread overuse of antimicrobials. Natural phytochemicals have proven to be good alternatives to such synthetic agents.[6] Natural products like Curcuma zedoaria, calendula, aloe vera and other herbs have been used effectively to treat oral diseases in the past.[1]

Description of Punica granatum

Punica granatum belonging to family Punicaceae is more commonly known as pomegranate.[7] The genus name, Punica, was derived from the roman name for Carthage. The word Pomegranate means Apple (“pomum”) and seeded (“granatus”).[8]

The Punica granatum (hereafter referred to as pomegranate) is a large shrub which grows 12-16 feet, has many spiny branches with lance shaped glossy leaves. The bark of the tree turns gray as the tree ages. The flowers are large, red, white, or variegated having a tubular calyx that eventually becomes the fruit. The ripe fruit is about five inches wide with a deep red, leathery skin, grenade shaped with a pointed calyx. The fruit contains many seeds separated by white, membranous pericarp. Each seed is surrounded by tart and red juice.[8]

Phytochemistry and functional components

Pomegranate juice contains anthocyanins, glucose, ascorbic acid, ellagic acid, gallic acid, caffeic acid, catechin, epigallocatechin, quercetin, rutin, iron and amino acids possessing anti-atherosclerotic, antihypertensive, antiaging and potent antioxidative properties. Seed oil is composed mainly of punicic acid and sterols having nephroprotective properties. The pericarp (peel, rind) contains punicalagins, flavones, flavonones, and other flavanols possessing anti-inflammatory, antimutagenic and antifungal activity. Tannins including punicalin and punicafolin, and flavones glycosides like luteolin and apigenin, form the major constituents of pomegranate leaves.[9] The leaves are said to have excellent antioxidant properties.[10] The flowers contain ursolic acid, triterpenoids like maslinic acid and asiatic acid possessing antioxidant, hepatoprotective properties and are used as a remedy for diabetes mellitus.[911] Ellagitannins and piperidine alkaloids are present in pomegranate roots and bark. The bark possesses molluscicidal properties.[9] The bark and roots are known for its antihelmintic and vermifuge properties.[12] The most beneficial components of pomegranate are ellagitannins, punicic acid, flavonoids, anthocyanidins, anthocyanins and estrogenic flavones.[9]

General therapeutics of pomegranate

Pomegranate is considered “A pharmacy unto itself”.[8] Pomegranate has many potential effects including bactericidal, antifungal, antiviral, immune modulation, vermifuge, stimulant, refrigerant, astringent, stomachic, styptic, laxative, diuretic and antihelminthic. It has also been widely used in treatment of cardiovascular diseases, diabetes, diarrhea, dysentery, asthma, bronchitis, cough, bleeding disorders, fever, inflammation, acquired immune deficiency syndrome, dyspepsia, ulcers, bruises, sores, mouth lesions, skin lesions, malaria, prostate cancer, atherosclerosis, hypertension, hyper lipidemia, denture stomatitis, male infertility, vaginitis, erectile dysfunction, Alzheimer's disease, obesity, and neonatal hypoxic-ischemic brain injury.[681314]

Periodontal implication of pomegranate

Dental plaque is a prerequisite for periodontal disease. Bacteria present in dental plaque have direct pathologic effect on the periodontal tissues. Periodontitis has been proven to occur due to various other indirect mechanisms apart from the direct effect of periodontal pathogens.[15] Bacterial lipopolysaccharides stimulate production of catabolic cytokines and inflammatory mediators including arachidonic acid metabolites such as prostaglandin E2 (PGE2), Interleukin-1 (IL-1), Interleukin-6 (IL-6), TNF–α (Tumour Necrosis Factor–α). These cytokines and inflammatory mediators stimulate the release of tissue-derived enzymes, the matrix metalloproteinases, which cause destruction of the extracellular matrix and bone.[15]

Reactive oxygen species have also been considered as a major etiology of exaggerated inflammatory response in the pathogenesis of periodontitis. These reactive oxygen species along with direct tissue damage to the periodontium may also activate key nuclear transcription factors, such as receptor activator of nuclear factor kappa β (NF-κB) and Activated Protein-1 (AP-1). These nuclear transcription factors possess a positive effect on gene transcription for key pro-inflammatory mediators and osteoclastogenesis stimulation.[15]

The major ingredient of pomegranate fatty acids, punicic acid, is an excellent anti-inflammatory compound with a property to suppress prostaglandin production.[16] Cold pressed pomegranate seed oil has inhibited both cyclooxygenase and lipoxygenase enzymes in vitro. Both these are key enzymes in production of various inflammatory mediators.[8] Pomegranate fruit extract has a broad inhibitory effect on matrix metalloproteinaises (MMPs) expression and IL–1β induced tissue destruction.[8] Apart from the above mechanisms, anti-inflammatory effect of pomegranate could be due its immunoregulatory action on macrophages and T and B lymphocytes.[17]

Pomegranate extract exhibited anti-inflammatory activity through inhibition of NF-κB (nuclear factor kappa-B) activity and prevention of ERK-1 or ERK-2 (Mitogen activated protein kinase cascades) activation. It also decreased NO (nitric oxide) and PGE2 synthesis in human intestinal Caco-2 cells. Ellagic acid inhibited NF-κB activation through a mechanism independent of Iκ-B (inhibitor of nuclear factor kappa B) phosphorylation.[16] Blocking NF-κB, inflammatory cell signaling pathways that produce various destructive factors may be a potential strategy to prevent inflammation induced bone resorption and a promising mechanism to treat periodontitis.[1518] Oral ingestion of polyphenol rich extract of pomegranate fruit extract inhibited COX-1 and COX-2 enzymes. It also inhibited IL-1β induced NO and PGE2 production.[19] A significant reduction of gingival bleeding was observed after using a dentifrice containing pomegranate.[20] Pomegranate could be beneficial in treating periodontitis as it possesses excellent anti-inflammatory effect.

Pomegranate extracts have the ability to scavenge free radicals and decrease macrophage oxidative stress and lipid peroxidation.[8] Pomegranate could produce an anti-gingivitis effect as the flavonoids possess direct antioxidant properties[21] and indirect effects by enhancing the free radical scavenging activity of hepatic enzymes catalase, super oxide dismutase and peroxidase.[8]

Sastravaha et al. concluded in their preliminary study that local delivery with Centella asiatica and Punica granatum extracts following scaling and root planing showed significant improvements in pocket depth and attachment level compared to placebo. Punica granatum extract may provide a synergistic action in collagen stabilization as tannins have the affinity for proteins, thus, forming bonds with collagen fibers.[22] In their follow-up study, they observed there were significant improvement in the periodontal parameters and a decrease in the IL-1β and IL-6 compared to baseline.[23]

Pomegranate components could promote oral health, including reducing the risk of gingivitis. Thrice daily mouth rinsing with pomegranate extract dissolved in water increased the levels of antioxidant activity and decreased activities of aspartate aminotransferase.[24] Aspartate aminotransferase is considered an effective indicator of cell injury and is elevated among periodontitis patients.[25]

Protein levels in saliva are higher among periodontitis patients correlating with the plaque forming bacterial content. Saliva samples showed a significant decrease in protein levels after rinsing with pomegranate mouthwash indicating its antibacterial activity.[26]

Pomegranate flavonoids have shown antibacterial action in vitro against gingivitis causing microbes.[27] Streptococcus sanguis (S. sanguis) was sensitive to pomegranate extract and the inhibitory action was similar to chlorhexidine.[28] S. sanguis is known to be the initial colonizer in dental plaque formation.[4] The possible reason for this antibacterial effect are the tannins which increase bacteriolysis, interfere with bacterial adherence mechanisms onto the tooth surfaces.[28] In contrast, fruit bark extract of pomegranate showed better inhibition of growth of S. sanguis, Streptococcus sobrinus and Lactobacillus casei when compared to chlorhexidine.[29] A hydroalcoholic extract pomegranate mouthrinse decreased colony forming units of plaque forming bacteria by 84% against chlorhexidine (79% inhibition) among 60 healthy patients. Pomegranate extract also suppressed the ability of plaque forming microorganisms to adhere to the surface of tooth. Pomegranate may be a possible alternate for the prevention of formation and treatment of dental plaque.[30]

A 10% Punica granatum extract gel was not efficient in preventing dental plaque formation and gingivitis.[7] Whereas, a pomegranate gel (5g of carboxymethyl cellulose in 100mL of pomegranate juice) showed excellent anti-gingivitis effect and significant reduction in plaque scores when used as an adjunct to mechanical debridement.[1]

A recent study proved that pomegranate mouthwash had antibacterial efficacy against Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), which are the most important periodontal pathogens.[21] Punica granatum has shown antimicrobial activity against Eikenella corrodens, which is a secondary colonizer in the biofilm formation on the tooth surface significantly more than chlorhexidine.[31] Rinsing with 30 mL of pomegranate juice was effective in reducing colony forming units of dental plaque forming organisms by 32%.[32] Pomegranate mouthwash used two times daily for fifteen days resulted in more efficient reduction of gingival and bleeding on probing scores when compared to chlorhexidine.[33] Pomegranate gel when used as an adjunct with mechanical debridement was efficient in treating gingivitis with an improvement in the clinical and microbiological parameters.[1] Significant improvement was observed in plaque, gingival and bleeding indices among 92 patients who were instructed to use a toothpaste, which contained pomegranate along with various other herbs.[34] Pomegranate thereby could be an excellent adjunct to the conventional periodontal therapy as an anti-plaque agent due to its antibacterial properties.

Deep periodontal pockets are said to be associated with Helicobacter pylori (H. pylori) infection.[35] Increased levels of H. pylori has been detected from the oral cavities of patients with periodontitis.[363738] Pomegranate has demonstrated significant antibacterial activity against H. pylori.[39] Hence, pomegranate could be beneficial in treating periodontitis.

Pomegranate extracts have been found to be effective against herpes virus.[16] Recently, it has been suggested that herpes viruses could be a trigger for periodontal tissue destruction. Herpes viruses may initiate and accelerate progression of periodontitis due to its potential to stimulate cytokine release from host cells, impair host defense mechanisms, resulting in increased virulence of resident periodontopathic bacteria.[15] Hence, pomegranate with its antiviral property could cure periodontitis as well. A recent study concluded that pomegranate peel extract had a remarkable effect on Trichomonas tenax and could be used in the treatment of acute ulcerative gingivitis.[40]

Pomegranate extract is known for its wound healing properties. It is known to induce increased fibroblast migration and proliferation, formation of collagen and angiogenesis.[414243] 5%, 10% and 15% methanol peel extract ointment of pomegranate resulted in a complete and faster wound healing.[4144] The wound healing properties can be attributed to the presence of tannins and polyphenols.[45]

Quorum sensing is the capacity of bacteria present in a biofilm to communicate with each other. Dental plaque is a biofilm. Quorum sensing plays an important role in gene expression for development of antibiotic resistance, promoting growth of bacteria essential for biofilm and discouraging growth of competitors.[46] Interfering with quorum sensing signals could be a potential strategy for disease control.[47] Pomegranate extract inhibited quorum sensing in Chromobacterium violaceum (C. violaceum) and Pseudomonas aeruginosa. This was demonstrated by inhibition of violacein (purple pigment) production in C. violaceum and interference with swarming in Pseudomonas aeruginosa. Pomegranate may be a rich source of compounds to overcome pathogenic bacteria and development of antibiotic resistance.[48]

Pomegranate has positive effects on enteric probiotic bacteria.[47] It has shown enhanced growth of Bifidobacterium species and Lactobacillus species.[49] These probiotic microorganisms are known to have effect on periodontal pathogens by affecting their growth, adhesion and colonization.[50] They also decreased the IL-1 and TNF-α levels in the gingival crevicular fluid and interfered with the activity of tissue destructive enzymes like elastase, myeloperoxidase and metalloproteinase-3.[5152] Probiotic bacteria could be beneficial in treating periodontitis by decreasing the periodontal pathogen burden in the oral biofilm and strengthening epithelial barrier function, thus enhancing resistance to infections.[53]

Synergistic action was observed between methanolic pomegranate extract and antibiotics like chloramphenicol, gentamicin, tetracycline, ampicillin and oxacillin against Methicillin resistant staphylococcus aureus (MRSA).[54] The antibiotic activity of ciprofloxacin was enhanced by methanolic peel extract of pomegranate.[55] Pomegranate because of its property of improving antibiotic sensitivity could be a promising adjunct in the treatment of periodontitis.

Other uses of pomegranate in dentistry

A 10% topical pomegranate gel was efficient in reducing recurrent aphthous stomatitis pain and time for complete healing of ulcers. This was attributed to its anti-inflammatory, antioxidant and antimicrobial properties of pomegranate.[56] An 80% pomegranate peel extract lozenge was able to decrease gag reflex in soft palate up to 88.5% and in tonsils up to 92.5%. This effect could be due to the presence of tannins which have anesthetic effects.[57] A gel based Punica granatum bark extract was effective in treating denture stomatitis as effectively as miconazole.[58]

Streptococcus mutans (S. mutans) is considered as the chief dental caries causing pathogen. S. mutans has shown high sensitivity to pomegranate.[59] Pomegranate fruit extract gel was active against S. sanguis, S. mutans and Streptococcus mitis (S. mitis) by controlling their adhesion on to glass surface and that it could be used to prevent adherence of various microorganisms in the oral cavity.[60] In a recent in vitro study, pomegranate pulp extract gel showed highly significant inhibitory effect at 5%, 25%, 50% and 100% against S. mutans when compared to aloe vera and sorbitol. This action is probably due to the antimicrobial property of tannins.[61] Pomegranate could be a potential anticariogenic agent due to its property to inhibit S. mutans.

Safety of pomegranate

Pomegranate and its constituents have been consumed for centuries without adverse effects.[8] Studies of pomegranate constituents in animals at concentrations and levels commonly used in folk and traditional medicine did not indicate any toxic effects.[13] Pomegranate juice, oil or powdered extracts can be consumed by healthy individuals without high risk. No adverse effects on renal or liver function were observed in humans upon administration of up to 1420 mg/day of pomegranate fruit extract tablets.[62]

P450 enzymes play a pivotal role in the metabolism of various drugs. Pomegranate inhibited this enzyme resulting in altered drug pharmacokinetics of tolbutamide, carbamazepine and pentobarbital.[636465] Future studies should be directed with emphasis on bioavailability of compounds, effective and safe doses of pomegranate that can be used in dentistry.

CONCLUSION

In the recent years, the use of plants with preventive and therapeutic effects contributing to health care has increased. The reason probably for the growing interest in phytotherapy is development of microbial resistance to antibiotics, consumers becoming aware of the adverse effects associated with traditional antibiotics and studies proving that plants possess medicinal values. Pomegranate referred as the “Nature's power fruit” possesses a vast ethno-medical history and represents a phytochemical reservoir of heuristic medicinal value. Known for its potent antibacterial, antiviral, antioxidant, anti-inflammatory, wound healing, probiotic properties pomegranate could prove truly as a “Pharmacy unto itself” for the treatment of periodontal disease underscoring the need for more clinical research in this aspect.