Exploring the role of cranberry polyphenols in periodontits: A brief review.

Cranberry juice polyphenols have gained importance over the past decade due to their promising health benefits. The bioactive component, proanthocyanidins is mainly responsible for its protective effect. A lot has been said about its role in urinary tract infection and other systemic diseases, but little is known about its oral benefits. An extensive search was carried out in the PubMed database using the terms "cranberry polyphenols" and "periodontitis" together. The institute library was also thoroughly scrutinized for all relevant information. Thus, a paper was formulated, the aim of which was to review the role of high molecular weight cranberry fraction on oral tissues and periodontal diseases.

INTRODUCTION

Cranberry (Vaccinium macrocarpon), the native North American fruit has recently come into limelight owing to its numerous beneficial effects on health.

Widely grown in the peat bogs of the cooler north eastern part of North America, it is one of the three original fruits of the country, which grows as a vine or low trailing shrub, bears a red fruit and is acidic in taste.

In the globally functional food industry, the fruit cranberry is popularly known for its nutrient and antioxidant qualities and is extensively marketed to India and many other countries as “ superfruit” in the form of fresh produce, dried fruit, juice, jams, sauces, and encapsulated powders.[12]

Cranberry itself is a unique, rich source of several classes of bioactive flavonoids including flavanols, anthocyanins, and proanthocyanidins which confer it the significant therapeutic potential. The medicinal use of cranberry dates way back to the 17th century when it was a popular treatment for scurvy and gastric problems.[3]

Structure of “Proanthocyanidins”- the bioactive component of cranberries

The non- dialyzable fraction/material (NDM) produced by extensively dialyzing cranberry juice with other modifications is a product devoid of sugars and acids and contains 0.35% anthocyanins and 65.1% proanthocyanidins.[4]

Proanthocyanidins, refer to a larger class of polyphenols, called flavanols. More complex polyphenols, having the same polymeric building block, form the group of tannins.

In 1947, Prof. Jacques Masquelier, was the first to develop techniques for the extraction of proanthocyanidins from pine bark and grape seeds.[5] Proanthocyanidins are of two types: -type A found in cranberries, apricots, and peanut skin and type B, common in other berries.[67]

Proanthocyanidins from cranberry juice cocktail are composed of repeating epicatechin units with at least one A-type linkage (O7 C2) as compared to the B-type linkages found in other tannin-rich foods.[8] This particular structure of cranberries is thought to influence their biological activity and in fact has been considered as a prerequisite for the antiadhesion property.[9]

In periodontal diseases, periodontopathogens colonize the teeth and subgingival area which leads to induction of protective host responses.[10]

Nevertheless incessant stimulation of the host immune system by bacteria and their products starts a chain of host-mediated destructive processes which result in the accumulation of inflammatory mediators followed by persistent inflammation frequently associated with matrix metalloproteinases (MMPs)’-mediated tissue destruction.[11121314] Soluble and cell bound proteases produced by bacteria can also degrade tissue proteins and contribute to invasion of periodontal tissues.[1516]

Effect on caries

In oral diseases like caries and periodontitis, cranberries have shown therapeutic potential owing to their anti-adhesive and other anti-microbial properties.

An experimental work by Weiss in 1998 revealed that in vitro testing a high-molecular-weight cranberry constituent reversed the coaggregation of 49 of 84 coaggregating bacterial pairs (58%). It acted preferentially on pairs in which one or both members were gram-negative anaerobes. Thus, the anti-coaggregating cranberry constituent showed potential for altering the subgingival microbiota, resulting in adequate control of periodontal diseases.[17]

The polyphenolic fraction of the fruit reportedly repressed the formation of biofilms and acid production by cariogenic streptococci.[1819] Weiss and colleagues in 2004 incorporated the NDM fraction of cranberry in a mouth rinse and subjects who used it for 6 weeks reported fewer cariogenic Streptococcus mutans.[20] In yet another study, cranberry fraction demonstrated the deactivation of enzymes glucosyltranferase and fructosyltranferase. These enzymes, essential to the formation of glucan and fructan, helped the adhesion of streptococci to the tooth surface, thereby inhibiting plaque formation.[212223]

Effect on periodontal bacteria and host mechanisms

Experimentally, Labreque in 2006 and Yamanaka in 2008 revealed that the NDM fraction of cranberry hindered the colonization of by Porphyromonas gingivalis and Fusobacterium nucleatum in the gingival crevice. Besides, it also prevented the adhesion of P. gingivalis to various proteins including type I collagen thus reducing bacterial coaggregation in periodontal diseases.[1924]

Cranberries were reported to restrain the proteolytic activity of the red complex specifically the gingipain activity of P. gingivalis, trypsin like activity of Tanerella forsythia and chemotrypsin like activity of T. denticola.[25] Thus, it was suggested by many workers that this fruit had the potential to limit the multiplication of pathogens by restricting their growth resources from amino acids, peptides and also inhibit the tissue destruction mediated by bacterial proteinases.

Host macrophages liberate proinflammatory cytokines (IL-1β, TNF-α) following stimulation with bacterial lipopolysaccharides of Aggregatibacter actinomycetemcomitans, F. nucleatum, P. gingivalis, T. denticola and T. forsythia. Claims like the inhibition of these cytokines were also made by Bodet et al. in 2006.[4] The fraction seemed to act by hampering the cellular signaling proteins, leading to reduction in the regulation of activator protein 1 (AP-1). This protein (AP-1) is an important transcription factor for the genes coding for proinflammatory mediators.[425]

Inflammatory cells, namely macrophages and fibroblasts, produce various enzymes like MMPs and elastase which mediate tissue destruction. In vitro ELIZA study revealed that cranberry proanthocyanidins inhibited MMP responses in a dose-dependent fraction. The lipopolysaccharide-induced IL-6, IL-8, and PGE-2 responses of gingival fibroblasts were also subdued by treatment with the cranberry fraction as was Cyclooxygenase-2 expression.[26] Arrest of the catalytic activity of MMP1 and MMP9 was believed to be associated with a reduced phosphorylation of key intracellular kinases and inhibition of NF-kβ.P65 activity.[27]

Tipton et al. in 2012 suggested that cranberry components might inhibit the NF-κB and MMP-3 thus regulating aggressive periodontitis’ fibroblast inflammatory responses.[28] A-type cranberry proanthocyanidins (AC-PACs) also deflect the secretion of IL-8 and chemokine ligand five (CCL5). This anti-inflammatory effect was again associated with reduced activity of the NF-kβ.p65 pathway.[29]

In 2011, Tanabe investigated the effect of AC-PACs on osteoclast formation and bone resorption activity and concluded the following. AC-PACs up to 100 µg/mL were reported to be non toxic for osteoclastic cells. Tartarase resistance acid phosphatase (TRAP) staining evidenced a dose-dependent inhibition of osteoclastogenesis. More specifically, AC-PACs at 50 µg/mL caused a 95% inhibition of RANKL-dependent osteoclast differentiation. This concentration of AC-PACs also significantly increased the secretion of IL-8 (6-fold) and inhibited the secretion of both MMP2 and MMP9. Lastly, AC-PACs affected bone degradation mediated by mature osteoclasts by significantly decreasing the release of collagen helical peptides. This study suggested that AC-PACs could interfere with osteoclastic cell maturation and physiology as well as prevent bone resorption.[30]

Other uses

The extract from the juice of cranberry has also been helpful in preventing child and female urinary tract diseases by inhibiting the adherence of Escherichia coli in the urinary tract mucosa through their high-molecular-weight tannins.[313233]

The protective effects of cranberry juice in UTIs were once attributed to cranberry's high benzoic and quinic acid content, which the human body metabolizes into hippuric acid, a potent antibacterial.[34] While this may be a factor in cranberry's protective results, to achieve a concentration of hippuric acid in the urine that provides this bacteriostatic effect would require the average person to drink a minimum 1500 ml (over six to eight-ounce glasses) of cranberry juice per day an unlikely amount for the average person to consume.[3536]

Cranberry polyphenols have also been shown to deter human cancer cell line proliferation in the oral cavity, colon and prostate and reduce the risk of cardiovascular diseases.[37383940]

They have arrested the development of gastric ulcers by preventing the adherence of Helicobacter pylori in the gastric mucosa and combat the adherence and infectious capacity of influenza virus.[414243]

Dosage

Different doses and formulations of cranberry, including unsweetened cranberry juice, cranberry juice cocktail, and cranberry extract tablets, have been proposed in different studies. A recent randomized controlled trial has proposed that one tablet of concentrated cranberry extract (300 to 400 mg) twice daily, or 8 oz of pure unsweetened cranberry juice three times daily for 12 months is safe and effective as an antiadhesion and antimicrobial agent for gram-negative bacteria.[4445]

Contraindications and adverse effects

Cranberry has a record of safety, although specific long-term safety data are lacking. No significant herb-drug interactions have been reported.

A single study found that cranberry may increase the absorption of vitamin B12 in patients who also are taking proton pump inhibitors and that it may allow the kidneys to metabolize weakly alkaline drugs (such as antidepressants and opioids) more rapidly, thus reducing their effectiveness.[46]

A small study found a significant rise in urinary oxalate levels, prompting a caution that regular use of cranberry may increase the risk of kidney stone formation in patients with a history of oxalate calculi.[47]

CONCLUSION

Though cranberry does seem to be the “wonder drug” for many dental problems, it does have a few major glitches.

Drinking cranberry juice can no way be a substitute for the medical treatment or cure of UTIs, ulcers, or periodontal disease. Further study of the proanthocyanidin bioactive component of cranberry, including in vivo metabolism and bioavailability research, is necessary in order to determine the clinical applications for these compounds.

All the studies exhibiting the inhibition of bacterial adhesion or host inflammatory molecules by cranberry polyphenols have been conducted in vitro. Nothing conclusive can be said about how biological molecules may affect the same processes in the oral cavity. While Weiss and colleagues did experiment using a cranberry mouthwash which effectively inhibited caries formation, more clinical studies are undeniably required to substantiate the stated claims. The juice itself is acidic and requires sugar or other sweeteners which may contribute to demineralization and caries formation. Also, the contact time to drink a glass of cranberry juice is too short to benefit the teeth or soft tissues in any definitive manner.

Newer techniques need to be developed to incorporate the concentrated polyphenolic fraction in toothpastes, mouth rinses, and other oral hygiene products. Local drug delivery or impregnation in resorbable fibers which could be packed in the gingival sulcus may benefit the patient to some extent by preventing the destruction of host tissues due to inhibition of MMPs and other anti- inflammatory molecules.