Propolis: Alternative Medicine for the Treatment of Oral Microbial Diseases

Abstract

Bees are arthropods of Hymenoptera order and are classified into two groups based on their
type of life: solitary and social life. Propolis is produced by bees that live socially, from the
harvesting of products derived from plants and used to seal and protect the hive against
intruders and natural phenomena [1]. Propolis term derives from the Greek Pro, "opposite, the
entry" and polis, "city or community" [2,3]. Propolis is a natural substance collected by Apis
mellifera bees in several plant species. It has been used in folk medicine for centuries [2,4].
Characteristically, it is a lipophilic material, hard and brittle when cold, but soft, flexible and
very sticky when warm. Hence the name "beeswax" [5]. It has characteristic odor and shows
adhesive properties of oils and interact strongly with skin proteins [6]. The composition of
propolis is complex [7,8].

Full text

Chapter 7
Propolis: Alternative Medicine for the Treatment of Oral
Microbial Diseases
Vagner Rodrigues Santos
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/54003
1. Introduction
Bees are arthropods of Hymenoptera order and are classified into two groups based on their
type of life: solitary and social life. Propolis is produced by bees that live socially, from the
harvesting of products derived from plants and used to seal and protect the hive against
intruders and natural phenomena [1]. Propolis term derives from the Greek Pro, "opposite, the
entry" and polis, "city or community" [2,3]. Propolis is a natural substance collected by Apis
mellifera bees in several plant species. It has been used in folk medicine for centuries [2,4].
Characteristically, it is a lipophilic material, hard and brittle when cold, but soft, flexible and
very sticky when warm. Hence the name "beeswax" [5]. It has characteristic odor and shows
adhesive properties of oils and interact strongly with skin proteins [6]. The composition of
propolis is complex [7,8]. Some factors, such as the botanical origin of propolis and its time of
collection can influence the chemical composition of this resinous material [9]. The color of
propolis varies from yellowish green to dark brown, depending on location - savannah,
tropical forests, desert, coastal and mountainous regions - where it is produced. [10,11,12].
Propolis is used by bees to protect against the entry of microorganisms, fungi and bacteria in
the hive, and as a sealing material for preventing the entry of light and moisture inside. It is
also used to line the comb, to allow the deposition of eggs by the queen, and to embalm small
dead animals (beetles and insects) that usually bees could not take into the hive, preventing
its putrefaction.3,5,7].
Interest in the pharmacological action of natural products has grown and found significant
popular acceptance. Among these products, propolis has been highlighted due to its applica‐
bility in the food industry and cosmetics, to be used as the active ingredient in several products,
among which include toothpastes and skin lotions [13]. Also available in the form of a capsule
(pure or combined), extract (hydroalcoholic or glycolic acid), mouthwash (combined with
© 2012 Santos; licensee InTech. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

melissa, sage, mallow and / or rosemary), lozenges, creams and powders (for use in or gargling
internal use, once dissolved in water) [2].
Regarding the ethnobotanical aspect, propolis is one of the few "natural remedies" that
continue to be used for a long period by different civilizations [14]. Propolis is widely used in
popular medicine, especially in communities with inadequate public health conditions[15]. It
was noticed that it can be more effective and less toxic than certain compounds. Significant
decrease in H₂O₂-induced DNA damage in cultures treated with propolis demonstrated
antioxidant activity of phenolic components found in propolis may contribute to reduce the
DNA damage induced by H₂O₂ [16].
2. History
Propolis is a natural remedy that has been used extensively since antiquity. The Egyp‐
tians, who knew very well the anti-putrefactive properties of propolis, used it for em‐
balming [17]. It was recognized for its medicinal properties by Greek and Roman
physicians, such as Aristotle, Dioscorides, Pliny and Galen. The drug was used as an anti‐
septic and healing in the treatment of wounds and as a mouthwash, and its use in the
Middle Ages perpetuated among Arab doctors [2]. Also, it was widely used in the form
of ointment and cream in the treatment of wounds in battle field, because of their heal‐
ing effect. This healing propolis property known as "Balm of Gilead," is also mentioned in
the Holy Bible [18]. From the pharmacological point of view, propolis has been used as
solid; in an ointment based on vaseline, lanolin, olive oil or butter, and in the form of al‐
coholic extract and hydroalcoholic solution. The proportion propolis/carrier may vary, in
order to obtain bacteriostatic or bactericidal results [19]. In the 1980s and 1990s, a great
number of publications occurred worldwide, highlighting Japan in number of published
papers followed by Brazil and Bulgaria [6]. In Dentistry, there are studies investigating
the pharmacological activity of propolissome situations, such as gingivitis, periodontitis,
oral ulcers, pulp mummification in dogs' teeth and dental plaque and caries in rats [19].
Also, it has been used in dressings of pre and post-surgical treatment, oral candididosis,
oral herpes virouses and oral hygiene. There was also the investigation of antiseptic and
healing properties of propolis in subjects admitted to various hospitals and the results
were extremely positive [20]. Thus, this natural product revealed great interest for the
treatment of oral diseases [21]. Internationally, the first licensed commercial product con‐
taining propolis was registered in Romania in 1965. Worldwide, in the same period ana‐
lyzed, it was found a total of 239 commercial licenses. In the 1980s, commercial licenses
were predominant in the former USSR and satellite countries. Currently, 43% of commer‐
cial licenses are Japanese origin and 6.2% of them are products for dental treatment. In Ja‐
pan, the scientific productivity reported for propolis increased 660% between the 1980
and 1990 [22]. The global interest in propolis research increased considerably in relation
to its various biological properties [23-27]. Another incentive for conducting research on
propolis is a high value on the international market, mainly in Japan, where a bottle of
ethanol extract is sold at prices ten times higher than that prevailing in Brazil. Brazil is
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considered the third largest producer of propolis in the world, behind Russia and China
only. Japan’s interest for the Brazilian propolis is due to its therapeutic and organoleptic
properties, and also the presence of minor amounts of heavy metals and other environ‐
mental pollutants [28,29]. In the last thirty years, various studies and scientific research
were performed to clarify the medicinal properties attributed to propolis [30,31].
3. Classification / rating
There was an attempt to classify the Brazilian propolis into twelve types according to physical-
chemical properties and geographical reports. However, to date, only three types of propolis
had their botanical origin identified. The main types of botanical origin are South (three),
Northeast (six) and Southeast (twelve), and they were reported as resins from Populus sp.,
Hyptis divaricata and Baccharis dracunculifolia (Figure 5), respectively. An attempt to classify
propolis produced in Brazil according to botanical origin and chemical composition [32] has
recognized 12 different types. It was suggested that Hyptis divaricata is the resin source of
northeastern propolis, Baccharis dracunculifolia of southeastern propolis and poplar (Populus
nigra) of southern propolis. This study by Park et al. [32] is indicative that just stating that a
certain sample corresponds to ‘Brazilian propolis’ hardly means anything indicative of
physical, chemical and biological characteristics, because a wide diversity of propolis types
exist in a country as large as Brazil, housing a wide plant diversity and a complex honeybee
genetic variation [3]. The different compounds present in Brazilian propolis were identified
and quantified using high performance liquid chromatography (HPLC) technique. Established
the process of separation by liquid chromatography, capable of identifying the major compo‐
nents of propolis samples (primary marker). Through the technique of HPLC and quantifica‐
tion of compounds identified by it, it was established a classification for Brazilian propolis
based on the presence of markers (Table 1 and Table 2). The main feature of this classification
relates to the speed in which this product bee can reach the market, from the field to the
pharmaceutical and cosmetic industries, encouraging the use of these typing for the manu‐
facture of their medicines and cosmetics, with established quality control, since all of these
markers were separated in a concentration range types. That is, the classification is quantita‐
tive. Another important factor is that the classification will be possible to manufacture
pharmaceuticals, cosmetics and oral hygiene products knowing the propolis type used and
the quantities of bioactive components, features never reported before in publications and
patents on propolis [33]. The Brazilian Cerrado is one of the richest areas in Baccharis sp. These
plants are a group of woody perennial shrubs, which are dioecious with male and female
inflorescences appearing on separate plants. Of the 30 different species of Baccharis, Baccharis
dracunculifolia is the dominant source of propolis in southeastern Brazil (Sao Paulo State and
Minas Gerais State), where most of propolis based products sold are produced [34]. Recently,
it was founded a red type of propolis in hives located in mangrove areas in the Northeast. It
was observed that bees collect exudate from the surface of red Dalbergia ecastophyllum
(Linnaeus, Taubert) (Figure 6). Analysis and comparision of plant exudates and propolis
samples demonstrate that the chromatographic profiles are exactly the same as the one found
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for D. ecastophyllum [35]. The best way to find the plant origin of propolis would be by
comparing the chemical composition of propolis with the alleged plant origin [36]. World
Propolis constituents of are shown in Table 3.
4. Chemical composition
Table 1 and Table 2 show the chemical markers constituents of green and red Brazilian
propolis, respectively, while Table 3 shows the chemical composition of various types of
world propolis. The highest concentration of phenolic compounds was obtained using sol‐
vents with lower concentrations of ethanol and higher concentrations of crude propolis,
but the highest concentration of flavonoids in the extract was obtained with higher con‐
centrations of ethanol in the solvent [11]. Over 300 chemical compounds are described in
various propolis origins [22]. Among the chemicals constituents, we can include waxes,
resins, balsams, oils and ether, pollen and organic material. The proportion of these sub‐
stances varies and depends on the place and period of collection [5,37]. The collected
propolis in a bee hive, also known as crude propolis, in its basic composition, contains
about 50% of plant resins, 30% of beeswax, 10% essential oils, 5% pollen, 5% debris of
wood and earth [7,14,6]. Propolis also contains various organic acids, considerable
amount of minerals (including, manganese, zinc, calcium, phosphorus, copper), vitamins
B1, B2, B6, C and E, acids (nicotinic acid and pantothenic acid) and aminoacids [5,7,11,38].
These constitutive features may vary by region and period of the year [39, 40].
Nº Compounds mg/g
1 Coumaric acid 3.56
2 Cinnamic acid 1.66
3 Quercetin 1.38
4 Kaempferol 1.77
5 Isorhamnetin 0,91
6 Sakuranetin 5.57
7 Pinobanskin-3-acetate 13.92
8 Chrysin 3.51
9 Galangin 9.75
10 Kaempferide 11.60
11 Artepillin C
(3,5-diprenyl-4-hydroxycinnamic acid) 82.96
BGP from Baccharis dracunculifoila (SBN97). HPLC test (Park et al.) [32].
Table 1. Chemical constituents markers of Brazilian green propolis sample
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Number Compounds Contents (mg/g)
01 Rutin 0.7
02 Liquiritigenin 1.8
03 Daidzein 0.3
04 Pinobanksin 1.7
05 Quercetin 0.5
06 Luteolin 1.2
07 Dalbergin 0.4
08 Isoliquiritigenin 4.8
09 Formononetin 10.2
10 Pinocembrin 3.3
11 Pinobanksin-3-acetate 1.7
12 Biochanin A 0.5
from Dalbergia ecastophyllum (Alencar et al.) [41]
Table 2. Flavonoids and other chemical constituents of Brazilian red propolis
Compounds (percentage of content) Authors
Fatty and aliphatic acids
(24–26%) Flavonoids (18–20%) Microelements (0.5–2.0%)
Burdok et al. [7]
Maciejewicz et al [43]
Park et al. [32]
Kumazawa et al.[44]
Salatino et al. [3]
Ozkul et al.[45]
Eremia et al.[46]
Machado et al.[47]
Vandor-Unlu et al.[48]
Wang et al.[49]
Butanedioic acid (Succinic
acid) Astaxanthin Aluminum (Al)
Propanoic acid (Propionic
acid) Apigenin Copper (Cu)
Decanoic acid (Capric acid) Chrysin Magnesium (Mg)
Undecanoic acid Tectochrysin Zinc (Zn)
Malic acid Pinobanksin Silicon (Si)
D-Arabinoic acid Squalene Iron (Fe)
Tartaric acid Pinostrobin chalcone Manganese (Mn)
Gluconic acid Pinocembrin Tin (Sn)
α-D-Glucopyranuronic acid Genkwanin Nickel (Ni)
Octadecanoic acid (Stearic
acid) Galangin Chrome (Cr)
β-D-Glucopyranuronic acid Acacetin
9,12-Octadecadienoic acid Kaemferide
Tetradecanoic acid Rhamnocitrin
Pentanedioic acid 7,4’-dimethoxyflavone
Glutamic acid 5-hydroxy-4’7-dimethoxyflavone
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Compounds (percentage of content) Authors
2,3,4-trihydroxy butyric acid 5,7-
dihydroxy-3,4’dihydroxyflavone
Phosphoric acid 3,5-dihydroxy-7,4’-
dimethoxyflavone
Isoferulic acid
Sugars (15–18%) Others (21–27%)
Sorbopyranose Cyclohexanone
D-Erythrotetrofuranose 3-methyl,antitricyclo undec-3-en
10-one
D-Altrose Cyclohexane
D-Glucose Cyclopentene
Arabinopyranose 5-n-propyl-1,3
dihydroxybenzene
d-Arabinose Butane
α-D-Galactopyranose 2(3H)-Furanone
Maltose L-Proline
α-D-Glucopyranoside 2-Furanacetaldehyde
D-Fructose 2,5-is-3-phenyl-7-
pyrazolopyrimidine
Aromatic acids (5–10%) Esters (2–6%) Cliogoinol methyl derivative
Benzoic acid Caffeic acid phenethyl ester Fluphenazine
Caffeic acid 4,3-Acetyloxycaffeate 4,8-Propanoborepinoxadiborole
Ferulic acid, Cinnamic acid 1,3,8-Trihydroxy-6-
methylanthraquinone
Cinnamic acid 3,4 dimethoxy-trimethylsilyl ester 1-5-oxo-4,4-diphenyl-2-
imidazolin-2-yl guanidine
3-Methoxy-4-cinnamate 3,1,2-Azaazoniaboratine/
Piperonal
Cinnamic acid 4 methoxy 3 TMS ester 3-
Cyclohexene
2-propenoic acid methyl ester 1H-Indole
Alcohol and terpens (2–
3.3%) 1H- Vitamins (2–4%) Indole-3-one
Glycerol A, B1, B2, E, C, PP 2-Furanacetaldehyde
Erythritol Guanidine
α-Cedrol 2(3H)Furanone
Xylitol 1,3,8-trihydroxy-6-
meyhylanthraquinone
Germanicol
Stigmast-22-en-3-ol
Pentitol
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Compounds (percentage of content) Authors
Ribitol
Vanilethanediol
Bicyclohept-3-en-2-ol
Farneso
Table 3. Propolis constituents according to Shawicka et al.[42].
However, the plant determines the chemical composition of propolis [4,39,40]. Today there are
various substances known in propolis with distinct chemical structures from following classes:
alcohols, aldehydes, aliphatic acids, aliphatic esters, amino acids, aromatic acids, aromatic
esters, flavonoids, hydrocarbohydrates esters, ethers, fatty acids, ketones, terpenoids, steroids
and sugars [21].The first studies to identify the active elements of propolis were performed in
1911 by researchers in Germany [50]: vanillin, cinnamic acid and alcohol. In the 1970s, [51]
succeeded in isolating and identifying eleven elements, especially the most important type
flavonoids, mainly flavones, flavonols and flavonones, terpenes, alpha-aceto butilenol and
isovanillin. At the same time, [52] it was identified the unsaturated aromatic acids such as
caffeic and ferulic acids. In the same decade, Kadakov et al.[53] reported the presence of
thirteen amino acids in samples of propolis. The therapeutic effects are attributed to various
phenolic compounds whichmake up the green propolis, which are widely distributed in plant
kingdom. These flavonoids can be considered the main compounds [7,8], and also some
phenolic acids and their esters, phenolic aldehydes, alcohols and ketones [54]. Flavonoids and
caffeic acid phenethyl ester (CAPE) are phenolic compounds which have the ability to inhibit
the growth and cell division and to increase membrane permeability interfering with microbial
cell motility [13]. Despite being the most studied components of propolis, flavonoids are not
solely responsible for the pharmacological properties. Several other components have been
related to the medicinal properties of propolis [55]. Propolis from Europe and China contains
many flavonoids and phenolic acids esters. Flavonoids are present only in small quantities in
Brazilian propolis. The major components of propolis of Brazilian origin are terpenoids and
ñ-coumarin prenylated acid derivatives [39]. In Southeastern Brazil there is plenty of the
botanical species for production of green resin, which is the Baccharis dracunculifolia, also called
"Rosemary's field", or "broom", which is a plant species typical of the Americas, due to the
necessity of acid soil to grow. Rosemary easily develops in Brazil, both in planted areas and
in abandoned spaces [34, 3,56]. The biodiversity needs to be investigated as a source of new
bioactive substances, such as cinnamic acid derivatives, especially artepilin C, flavonoids and
other pharmacological or functional properties [36].The renewed interest on the composition
of Brazilian propolis is due to the fact that Brazil has a very diverse flora, tropical climate and
Africanized Apis mellifera bees species that produce propolis during the period from April to
September [5,32]. The typical constituents of Brazilian green propolis from Baccharis dracun‐
culifolia are derived prenylated cafeochemic acid and cinnamic acid derivatives, such as
artepilin C and baccharin. Brazilian green propolis is chemically different because it contains
not only prenylateds of cinnamic acid, but also triterpenoid [57]. In dealing with the chemical
composition and biological activity of green propolis, one can not point to a component of a
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particular substance or class of substances that could be responsible for their distinct phar‐
macological activities. Isoliquiritigenin, liquiritigenin and naringenin, isoflavones, isoflavans
and pterocarpans were detected in Cuban Red Propolis, Brazilian Red Propolis (BRP) and
Dalbergia ecastophylum extract (DEE), whereas polyisoprenylated benzophenones guttiferone
E/xanthochymol and oblongifolin A were detected only in BRP. Pigments responsible for the
red color of DEE and red propolis were also identified as two C30 isoflavans, the new retusa‐
purpurin A and retusapurpurin B [10]. Obviously, different samples at different combinations
of substances are essential for the biological activity of propolis [58,14]. It is important to note
that all investigations on the antibacterial activity of specific substances isolated from propolis
showed that a single component does not have an activity greater than the total extract [59].
The chemical properties of propolis are of great relevance considering its pharmacological
value as a natural mixture and as a powerful source of new antimicrobial agents, antifungal,
antiviral and individual compounds [58, 60].
5. Therapeutic properties of propolis
Currently, it is known that Brazilian propolis shows several biological activities, such as
antimicrobial, antiinflammatory, immunomodulatory, among others [12]. The composition of
propolis is very complex. We can observe the following: antibacterial activity, conferred by
the presence of flavonoids, aromatic acids and esters in its composition; bactericidal action
resulting from the presence of cinnamic acid and coumarin; in vitro antiviral activity (herpes
simplex, influenza), due to the action of flavonoids and aromatic acids derivatives, antiulcer
(assistance in healing), immunostimulating, hypotensive and cytostatic actions [21]. The
methods of extraction of propolis may influence its activity, from different solvents at different
soluble extract components [6,61]. The composition of propolis can vary according to the
geographic locations from where the bees obtained the ingredients. Two main immunopotent
chemicals have been identified as caffeic acid phenethyl ester (CAPE) and artepillin C. CAPE
and artepillin C have been shown to exert immunosuppressive function on T lymphocyte
subsets but paradoxically they activation macrophage function. On the other hand, they also
have potential antitumor properties by different postulated mechanisms such as suppressing
cancer cells proliferation via its anti-inflammatory effects; decreasing the cancer stem cell
populations; blocking specific oncogene signaling pathways; exerting antiangiogenic effects;
and modulating the tumor microenvironment[62]. The good bioavailability by the oral route
and good historical safety profile makes propolis an ideal adjuvant agent for future immuno‐
modulatory or anticancer regimens. However, standardized quality controls and good design
clinical trials are essential before either propolis or its active ingredients can be adopted
routinely in our future therapeutic armamentarium [62].
5.1. Anti-inflammatory activity
As an anti-inflammatory agent, green propolis is known to inhibit the prostaglandin synthesis,
activate the thymus gland, help the immune system by promoting the phagocytic activity,
stimulating cellular immunity, and increasing healing effects on epithelial tissue. Additionally,
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the propolis contains elements such as iron and zinc, which are important for the synthesis of
collagen [63,35]. Recently it was reported that Artepillin C has an inhibitory effect on nitric
oxide and prostaglandin E2 by modulating NF-êâ using the macrophage cell line RAW 264.7
[64]. The anti-inflammatory activity observed in green propolis seems to be due to the presence
of prenylated flavonoids and cinnamic acid. These compounds have inhibitory activity against
cyclooxygenase (COX) and lipooxygenase. It also appears that the caffeic acid phenethyl ester
(CAPE) has anti-inflammatory activity by inhibiting the release of arachidonic acid from
cellular membrane, removing the activities of COX-1 and COX-2 [65, 66]. Propolis also exhibits
anti-inflammatory effects against models of acute and chronic inflammation (formaldehyde
and adjuvant-induced arthritis, carrageenin and PGE 2, induced paw edema and granuloma
pellete cotton). The exact mechanism of anti-inflammatory action of propolis is still unclear [2].
Treatment with 50 µM CAPE significantly reduced the levels of leptin (p<0.05), resistin (p<0.05)
and tumor necrosis factor (TNF)-alpha (p<0.05) which are known to aid adipocytokines
production in adipocytes. CAPE has inhibitory effects on 3T3-L1 mouse fibroblast differen‐
tiation to adipocytes. In 3T3-L1 cells, treatment of CAPE decreased the triglyceride deposition
similar to resveratrol, which is known to have an inhibitory effect on 3T3-L1 differentiation to
adipocytes. In conclusion, we found that CAPE suppresses the production and secretion of
adipocytokines from mature adipocytes in 3T3-L1 cells [67]. The crude hexane and dichloro‐
methane extracts of propolis displayed antiproliferative/cytotoxic activities with IC50 values
against the five cancer cell lines ranging from 41.3 to 52.4 µg/ml and from 43.8 to 53.5 µg/ml,
respectively. Two main bioactive components were isolated, one cardanol and one cardol, with
broadly similar in vitro antiproliferation/cytotoxicity IC(50) values against the five cancer cell
lines and the control Hs27 cell line, ranging from 10.8 to 29.3 µg/ml for the cardanol and < 3.13
to 5.97 µg/ml (6.82 - 13.0 µM) for the cardol. Moreover, both compounds induced cytotoxicity
and cell death without DNA fragmentation in the cancer cells, but only an antiproliferation
response in the the non-transformed human foreskin fibroblast cell line
(Hs27, ATCC No. CRL 1634) used as a comparative control.However, these compounds did
not account for the net antiproliferation/cytotoxic activity of the crude extracts suggesting the
existence of other potent compounds or synergistic interactions in the propolis extracts. This
is the first report that A. mellifera propolis contains at least two potentially new compounds (a
cardanol and a cardol) with potential anti-cancer bioactivity. Both could be alternative
antiproliferative agents for future development as anti-cancer drugs [68].
5.2. Antimicrobial activity
5.2.1. Antibacterial and antifungal activity
Previous studies have shown that green propolis extracts inhibit the in vitro growth of
Streptococcus mutans [5,69,8,59]. This microorganism is etiologically related to the formation of
dental caries in humans and animals. Propolis showed efficient antimicrobial activity against
Pseudomonas sp and Staphylococcus aureus [70]. Propolis antimicrobial effect is directly propor‐
tional to its concentration [54]. Propolis ethanolic extracts exhibited significant antimicrobial
activity against many pathogens from the oral cavity, including Porphyromonas gingivalis,
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Prevotella intermedia, Tannerella forsythia, Fusobacterium nucleatum [(69,24,71], which is the main
microbiota involved in periodontal disease related to plaque. Gram-positive bacteria are more
sensitive than Gram-negative bacteria to propolis extracts [72]. So far, no data is available to
answer this observation. Gram-negative bacteria have a cell wall chemically more complex
and a higher fat content, which may explain the higher resistance [73,74]. Antibacterial activity
of green propolis derives mainly of flavonoids, aromatic acids, esters present in resins,
galangin, pinostrobin, and pinocembrin which have been known as the more effective agents
against bacteria. Ferulic acid and caffeic acid also contribute to the bactericidal action of
propolis [5]. A simple analogy can not be made to the mode of action of classic antibiotics.
There are no reports considering the resistance to bacterial constituents of propolis, and these
properties may influence the success of antibiotic therapy in the oral cavity [63]. The solvent
used for propolis extraction (ethanol, chloroform, methanol, propylene glycol, for example)
can influence its antimicrobial activity. In fact, oily preparations have high antimicrobial
activity, while solutions of glycerin showed little inhibition of Gram-positive and ethanolic
solutions and propylene glycol showed good activity against yeasts [74]. Several studies have
reported synergistic activity of propolis associated with various antibiotics, including activity
against strains resistant to benzylpenicillin, tetracycline and erythromycin. These studies
concluded that propolis has significant synergistic action, which may constitute an alternative
therapy for microbial resistance, but dependent on its composition [75,9,76]. Propolis has also
shown fungistatic and fungicidal activity in vitro against yeasts identified as cause of onycho‐
mycosis [35]. Although propolis is not widely used in conventional health care, is recom‐
mended for use as home remedies in the treatment of oral candidosis, denture stomatitis and
skin lesions by numerous books and articles in the popular press [77,78]. Although some
studies have focused on showing the antifungal activity of propolis extract, few have shown
their effects on morphology and structure of Candida albicans [79,80]. Combinations of some
drugs, antimycotic with propolis (10%) increase their activity against the yeast Candida
albicans. The greatest synergistic effect against various strains were obtained when propolis is
combined with other antifungal agents [5]. Siqueira et al.[81] demonstrated the antifungal
activity of aqueous and alcoholic extracts of the green propolis and the alcoholic extract of red
propolis was observed against Trichophyton rubrum, Trichophyton tonsurans and Trichophyton
mentagrohytes samples, using as controls itraconazole and terbinafine. The data obtained
showed that the green propolis alcoholic extract's antifungal activity was from 64 to 1024 µg/
mL. The antifungal activity of red propolis alcoholic extract was more efficient than the green
propolis alcoholic extract for all three species studied. The antifungal potential of the alcoholic
extracts of green and red propolis demonstrated suggest an applicable potential as an alter‐
native treatment for dermatophytosis caused by these species [82, 81]. On the other hand the
diterpenes: 14,15-dinor-13-oxo-8(17)-labden-19-oic acid and a mixture of labda-8(17),13E-
dien-19-carboxy-15-yl oleate and palmitate as well as the triterpenes, 3,4-seco-cycloart-12-
hydroxy-4(28),24-dien-3-oic acid and cycloart-3,7-dihydroxy-24-en-28-oic acid were isolated
from Cretan propolis. All isolated compounds were tested for antimicrobial activity against
some Gram-positive and Gram-negative bacteria as well as against some human pathogenic
fungi showing a broad spectrum of antimicrobial activity [83]. Concerning the antimicrobial
activity of propolis phenols, Candida albicans was the most resistant and Staphylococcus aureus
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the most sensitive from Portugal, Braganca and Beja`s propolis. The reference microorganisms
were more sensitive than the ones isolated from biological fluids [84]. Tables 4, 5, 6, and 7 show
results from in vitro antimicrobial activity of ethanolic extract and gel containing Brazilian
green propolis. Imaging studies with electron microscopy suggest the rupture of the cell wall
of Candida albicans as one of the mechanisms of action of Brazilian green propolis (Figure 1) [78].
Figure 1. Micrographs showing C. albicans treated for 24h with subinhibitory concentrations of Brazilian Green Propo‐
lis extract (BGP). Scanning electron micrographs: Treated (panels A, B, and C) and untreated (panel D). A and B: cell
wall detachment. C: cell agglomeration. Mello et al. [78].
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Microorganisms MIC (ìg/mL) MBC (ìg/mL) Inhibition zones (M±SD
=mm)
C. albicans 20-50 100-300 16.3±0.52
C. tropicalis 20-50 100-300 12.3±0.08
C. glabrata 20-50 100-300 15.6±0.50
C. krusei 20-50 100-400 28.3±0.15
C. parapsilosis 20-50 100-400 18.6±0.08
C. guilliermondii 20-50 100-400 12.6±0.57
S. mutans 25-50 200-400 18.3±1.15
S. sobrinus 25-50 200-400 28.6±0.57
P. intermedia 20-50 200-400 17.5±2.50
T. forsythensis 30-60 300- 500 14.0±0.00
B. fragilis 25-50 300-500 15.3±1.15
S. aureus 25-50 200-400 16.3±2.08
P. gingivalis 30-50 200-400 14.0±0.00
F. nucleatum 30-60 200-400 15.2±0.26
F. necrophorum 30-60 200-400 17.3±0.57
A. actinomycetemcomitans 30-60 200-400 14.6±0.57
Table 4. Minimum Inhibitory Concentration (MIC); Minimum Bactericidal Concentration (MBC), Means and Standard
Deviation (M±SD) of diameter inhibition zones obtained in agar diffusion test using Brazilian Green Propolis Extract
(BGP) against Candida spp., Gram positive and Gram negative oral pathogenic bacteria. (Tests in triplicate).Paula et al.
[59]
Microorganisms Propolis MIC
(ìg/ml)
Nystatin MIC
(ìg/ml)
Chlorexidine
MIC (ìg/ml)
Tetracycline
MIC (ìg/ml)
C. albicans 14.00 16.00 _ _
C. tropicalis 14.00 16.00 _ _
S. mutans 28.00 _ 8.00 1.00
S. aureus 14.00 _ 32.00 4.00
A. israelii 1.75 _ 32.00 4.00
E. faecalis 7.00 _ - 16.00 2.00
A. actnomycetemcomitans 3.50 _ 8.00 1.00
Table 5. Minimum Inhibitory Concentration (MIC) of propolis ethanolic extract and control obtained for each strain
tested. Tests in quadruplicates. (Paula et al.) [59].
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Propolis
ointment %
Tetracycline
1%
Bacteria
48 hs
activity
7 days
activity
48h 7days
5% 10% 15% 20% 5% 10% 15% 20%
S. mutans 13.33±3.09 19.00±2.00 19.66±2.08 23.33±1.52 9.66±1.52 15.66±2.58 14.33±2.08 18.33±1.52 14.33±0.57 9.33±1.52
S. aureus 13.00±1.00 17.66±2.08 18.66±2.08 21.66±0.57 9.66±0.57 12.33±1.15 14.00±1.00 15.00±2.00 18.33±2.51 11.00±1.53
A. israelii 12.00±1.00 14.66±2.08 15.00±2.08 21.66±2.51 7.33±1.15 9.66±2.08 11.66±2.08 13.66±1.52 14.00±1.73 10.00±1.00
E. faecalis 14.66±1.15 18.33±0.57 21.00±1.00 24.00±1.00 9.66±0.57 11.00±1.00 12.66±0.57 15.00±1.00 9.66±2.08 7.66±1.15
A.a.14.33±1.52 18.00±2.00 21.66±2.08 25.33±2.08 8.66±2.51 11.00±2.00 14.33±1.52 13.66±1.52 18.00±2.00 12.00±1.00
Table 6. Susceptibility of oral bacteria to Brazilian propolis adhesive formulation. Inhibition zones values in mm (M
±SD; n=3). Negative control was inactive..A.a. = A. actinomycetemcomitans (Santos et al.) [71]
Fungi
Propolis
ointment %
Nystatin 5%
48 h activity 7 day activity 48 h 7day
5% 10% 15% 20% 5% 10% 15% 20%
C. albicans 16.33±1.52 21.66±1.57 23.00±1.00 26.00±1.00 12.33±1.52 17.00±1.00 16.66±1.52 20.66±0.57 12.00±2.00 8.66±1.52
C. tropicalis 16.66±2.51 24.33±2.03 23.00±2.00 26.00±2.00 13.33±2.08 19.33±0.57 17.66±0.57 19.00±1.00 14.66±1.52 10.66±1.52
Table 7. Susceptibility of Candida species to Brazilian propolis adhesive formulation. Inhibition zones values in mm (M
±SD; n=3). Negative control was inactive. (Santos et al.) [71]
5.2.2. Antiviral activity
There are many reports on the antiviral activity of propolis. In a study performed in Ukraine
compared the efficacy of ointment with propolis Canadian ointments acyclovir and placebo
(vehicle) in treating subjects with type 2 Herpes applicant. The preparation of propolis
containing flavonoids found to be more effective than the other two in wound healing and
reduction of local symptoms [98]. The cytotoxic and antiherpetic effect of propolis extracts
against HSV-2 was analysed in cell culture, and revealed a moderate cytotoxicity on RC-37
cells. However both propolis extracts exhibited high anti-herpetic activity when viruses were
pretreated with these drugs prior to infection. Selectivity indices were determined at 80 and
42.5µg/mL for the aqueous and ethanolic extract, respectively, thus propolis extracts might be
suitable for topical therapy in recurrent herpetic infection [99]. Huleihel & Isanu [100] reported
potent antiviral activity of propolis against Herpes simplex-1 infection in vitro and in vivo. They
suggested that the propolis can prevent absorption of the virus within the host cells and
interfere with viral replication cycle. In vitro studies suggest that the green propolis has potent
antiviral activity against variants X4 and R5 HIV-1. Similar activity was observed with CD4 +
lymphocytes in operation, at least in part, as an inhibitor of viral entry [101,35]. Also, the
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antiviral activity of components of propolis, such as esters of cinnamic acids replacements was
studied in vitro [5, 9, 102]. The antiviral effect of propolis extracts and selected constituents,
e.g. caffeic acid, p-coumaric acid, benzoic acid, galangin, pinocembrin and chrysin against
herpes simplex virus type 1 (HSV-1) was analysed in cell culture by Schnitzler et al.[103]. The
50% inhibitory concentration IC50 of hydro ethanolic propolis extracts for HSV-1 plaque
formation was determined at 0.0004% and 0.000035%, respectively. Both propolis extracts
exhibited high levels of antiviral activity against HSV-1 in viral suspension tests, plaque
formation was significantly reduced by >98%. Both propolis extracts exhibited high anti-HSV-1
activity when the viruses were pretreated with these drugs prior to infection. Among the
analysed compounds, only galangin and chrysin displayed some antiviral activity. However,
the extracts containing many different components exhibited significantly higher antiherpetic
effects as well as higher selectivity indices than single isolated constituents. Propolis extracts
might be suitable for topical application against herpes infection [104]
5.3. Antioxidative activity
The antioxidative activity deserves special interest because propolis could be topically applied
successfully to prevent and treat skin damaged [85, 86, 87]. Phenolic compounds found in high
concentrations in Brazilian green propolis, including Artepillin C, have a wide range of
biological properties including the ability to act as an anti-oxidizing free radicals and nitric
oxide radicals and also the ability to interfere with the inflammatory response through
inhibition of iNOS and COX-2 activities [88]. Although studies of propolis ethanol extracts are
very common, it is reported that the aqueous extract has good antioxidant activity, associated
with high content of phenolic compounds [89,90,91, 92]. Some studies have indicated propolis
inhibiting superoxide anion formation, which is produced during autoxidation of â-mercap‐
toethanol [93,2]. The antioxidative activity of propolis and its main phenolic compounds,
caffeic acid, p-coumaric acid, ferulic acid, and caffeic acid phenethyl ester, were investigated
in yeast Saccharomyces cerevisiae. Yeast cells showed decreased intracellular oxidation, with no
significant differences seen for the individual phenolic compounds. Ethanol Extract Propolis
(EEP) antioxidative activity was also investigated at the mitochondrial proteome level and
changes in the levels of antioxidative proteins and proteins involved in ATP synthesis were
seen [94]. Brazilian green propolis is derived of B. dracunculifolia and protective effects of B.
dracunculifolia glycolic extract against oxidative stress in isolated rat liver mitochondria (RLM)
were investigated by Guimaraes et al.[95]. So, B. dracunculifolia exhibit potent antioxidant
activity protecting liver mitochondria against oxidative damage and such action probably
contribute to the antioxidant and hepatoprotective effects of green propolis [95]-. CAPE are
involved with the renal damage protection induced by Cd (II) owing to its antioxidant capacity
and anti-inflammatory effect [96]. Preadministration of Brazilian Propolis Ethanol Extract (50
or 100 mg/kg) to the stressed rats protected against the hepatic damage and attenuated the
increased hepatic lipid peroxide and NO(x) contents and myeloperoxidase activity and the
decreased hepatic non-protein SH and ascorbic acid contents and superoxide dismutase
activity, possibly through its antioxidant and antiinflammatory properties [97].
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5.4. Antitumoral activity
Several researchers reported the antitumoral property of propolis in vitro and in vivo [105,106,
30, 68]. Propolis isolated components showed antiproliferative activity in tumor cells [6].
Artepilin C, the major component of Brazilian green propolis, has antiangiogenic activity.
Propolis may suppress tumor growth in vivo, but these mechanism effects is not completely
understood [107, 39, 60]. Propolis shows antitumor properties, and its anticarcinogenic and
antimutagenic potential is promising, but the mechanisms involved in chemoprevention are
still unclear [108]. On other hand, CAPE and chrysin may be useful as potential chemothera‐
peutic or chemopreventive anticancer drugs [42]. However, the human aldo-keto reductase
(AKR) 1C3, also known as type-5 17â-hydroxysteroid dehydrogenase and prostaglandin F
synthase, has been suggested as a therapeutic target in the treatment of prostate and breast
cancers was inhibited by Brazilian propolis-derived cinnamic acid derivatives that show
potential antitumor activity, and it was found that baccharin a potent competitive inhibitor
(K(i) 56 nM) with high selectivity [109]. There are currently several authors studied the
antitumor activity of propolis, especially its components. Some initial studies are, however,
some authors already have in-depth evaluation of about the propolis activity onto various
animal or human types of tumor cell lines [110-115].
5.5. Immunomodulatory activity
The immunomodulatory activity of propolis is one of the most studied areas in conjunction
with its anti-inflammatory property [116-120]. The immunomodulatory action of propolis
seems to be limited to macrophages, with no influence on the proliferation of lymphocytes
[121]. The inhibitory effect of green propolis (5-100µg/mL) on splenocyte proliferation was
observed in vitro [122], and previous studies demonstrated that flavonoids have an immuno‐
suppressive effect in lymphoproliferative response [123-125]. Since, propolis contains flavo‐
noids, that may explain the reported effect [6,10]. Another explanation for the inhibitory effect
on lymphocyte proliferation from the observation that both CAPE has inhibitory effects on
transcription of nuclear factor-êB (NF-êB) (p65) and nuclear factor of activated T-cells (NFAT).
Consequently, CAPE inhibited IL-2 gene transcription, IL-2R (CD25) expression and prolifer‐
ation of human T cells, providing new insights into the molecular mechanisms involved in
inflammatory and immunomodulatory activities of this natural component [6]. Green propolis
exhibited immuno-stimulatory and immunomodulatory effects on CD4/CD8T cells and on
macrophages in vitro and in vivo mice [126]. Propolis administration to melanoma-bearing mice
submitted to stress stimulated IL-2 expression, as well as Th1 cytokine (IL-2 and IFN-ã)
production, indicating the activation of antitumor cell-mediated immunity. Also, propolis
stimulated IL-10 expression and production, which may be related to immunoregulatory
effects indicating its antitumor action in vivo [127]. On other hand, Orsatti and Sforcin [128]
demonstrated the propolis immunomodulatory action in chronically stressed mice, upregu‐
lating TLR-2 and TLR-4 mRNA expression, contributing to the recognition of microorganisms
and favoring the initial steps of the immune response during stress. A new line of research
involving propolis is the possible application as a vaccination adjuvant, although most
commercial vaccines use aluminum salts to this end. A sample of green Brazilian propolis was
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tested, together with other adjuvant compounds, to immunize mice against inactivated swine
herpes virus (SuHV-1). When administered together with aluminum hydroxide, the propolis
extract increased both cellular and humoral responses [103].
6. Toxicity
It must be emphasized that propolis has the advantage of being a natural product, with a
higher molecular diversity. It has many therapeutic substances compatible with the me‐
tabolism of mammals in general, which reduces the possibility of causing adverse reac‐
tions to oral tissue as compared to industrial products tested [13]. The aqueous and
alcoholic extracts of propolis do not cause irritation to the tissues [17] and are considered
relatively toxic [7]. Experimental mouthwash solutions containing propolis showed no sig‐
nificant inhibitory activity of microorganisms as effective as chlorhexidine, but found low‐
er cytotoxicity on human gingival fibroblasts; propolis is relatively non-toxic and studies
have exhibited a no-effect level in a mice study of 1400 mg/kg weight/day leading the au‐
thors to propose that a safe dose in humans would be 1.4 mg/kg weight/day, or approxi‐
mately 70 mg/day [63]. On other hand, Pereira et al. [29] demonstrated high effectiveness
of mouthwash containing propolis in control of dental plaque and gingivitis in humans
and not observed no toxic or side effects in the administration of the rinse during 90
days. Propolis is considered safe in small doses. Therefore, adverse effects are common at
doses above 15g/day. The most commonly experienced adverse effects are allergic reac‐
tions, as well as irritation of the skin or mucous membranes [129]. Caution should be
used in the treatment of individuals with asthma and eczema and nettle rash [2].
7. Standardization
A universal chemical standardization of propolis would be impossible. Therefore, a detailed
investigation of its composition, botanical origin and biological properties is significant [6]. It
was postulated that different propolis may have different chemical and pharmaceutical
properties. In this sense, standardization of propolis is required. Most studies on the chemistry
of propolis include those directed to the European propolis composed of Populus sp. These
studies have been conducted by paired with Gas Chromatography Mass Spectrometry (GC-
MS). Therefore, due to the lower reproducibility of these methods, the use of High- Perform‐
ance Liquid Chromatography (HPLC) is currently recommended [22,130,131]. An alternative
method, using electro-spray, was recently tested to determine the patterns and content of
polyphenolic components of propolis [132]. Nuclear magnetic resonance is one of the best
detection methods because it recognizes components sensitive or insensitive to Ultraviolet
Light (UL) [133,134]. Standardization can prevent product adulteration. Therefore, the
methods used to extract components of propolis require adequate standardization [22, 87,135].
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8. Oral clinical studies
Several clinical studies have demonstrated propolis efficacy in clinical trials, but the majority
of studies involve topical application [20, 136-138]. The great diversity and the complexicity
of chemical components makes difficult to standardize and to research the mechanisms of
action. It is known the propolis anti-inflammatory, anti-microbial, analgesic, antioxidant, and
antitumorproperties. Recently, some authors have demonstrated the properties of some
components, however, one can not consider when using propolis but as a whole. The antimi‐
crobial activity, for example, may be effective when considering the synergism between the
components. Moreover, there was always the concern of several authors to develop oral
mouthwashes- based propolis to control oral microbiota [138-140]. Koo et al.[141] demon‐
strated the effect of a mouthrinse containing selected propolis on 3-day dental plaque accu‐
mulation and polysaccharide formation and observed the Dental Plaque Index(PI) for the
experimental group was 0.78 (0.17), significantly less than for the placebo group, 1.41 (0.14).
On other hand, the experimental mouthrinse reduced the PI concentration in dental plaque by
61.7% compared to placebo (p < 0.05). The clinical efficacy of an alcohol-free mouthwash
containing 5.0% (W/V) Brazilian green propolis (MGP 5%) for the control of plaque and
gingivitis were demonstrated by Pereira et al.[29] (Tables 8, 9, 10, and 11). Twenty five subjects,
men and women aging between 18 and 60 years old (35 ± 9), were included in a clinical trial`s
phase II study of the patients who had a minimum of 20 sound natural teeth, a mean plaque
index of at least 1.5 (PI), and a mean gingival index (GI) of at least 1.0. They were instructed
to rinse with 10mL of mouthwash test for 1 minute, immediately after brushing in the morning
and at night. After 45 and 90 days using mouthwash, the results showed a significant reduction
in plaque and in gingival index when compared to samples obtained in baseline. These
reductions were at 24% and 40%, respectively (P <0.5). There were no important side effects in
soft and hard tissues of the mouth.
Baseline 45 days 90 days Reduction %
MGP5% N=22
1.17 (0.20)
N=22
0.64 (0.24)
N=21
0.70 (0.18)
Baseline- 45 days
45*
Baseline- 90 days
40* 45 days – 90 days
Table 8. Mean scores of Gingival Index (DP) and percent reduction between periods (Pereira et al., 2011) [29].∗
Friedman test (ANOVA) P <.05.
Baseline 45 days 90 days Reduction-%
MGP5% n = 22
0.30 (0.17)
n = 22
0.08 (0.06)
n = 21
0.07 (0.03)
Baseline–45
days
73*
Baseline–90 days
77*
45 days–90 days
13 (ns)**
Table 9. Mean scores of Severity Gengival Index (DP) and percent reduction between periods (Pereira et al., 2011)
[29]. *Friedman test (ANOVA) P <.05. ∗∗Not significant.
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Baseline 45 days 90 days Reduction-%
MGP5% n = 22
2.39 (0.69)
n = 22
1.77 (0.61)
n = 21
1.82 (0.62)
Baseline–45
days
26*
Baseline–90 days
24*
45 days–90 days∗
______
Table 10. Mean scores of Plaque Index (DP) and percent reduction between periods (Pereira et al., 2011)
[29].∗Friedman test (ANOVA) P <.05.
Baseline 45 days 90 days Reduction-%
MGP5% n = 22
0.44 (0.19)
n = 22
0.26 (0.14)
n = 21
0.26 (0.15)
Baseline–45 days
41*
Baseline–90 days
41*
45 days–90 days
____
Table 11. Mean scores of Severity Plaque Index (DP) and percent between periods (Pereira et al., 2011) [29].∗
Friedman test (ANOVA) P <.05.
In this study, the MGP 5% showed evidence of its efficacy in reducing PI and GI. However, it
is necessary to perform a clinical trial, double-blind, randomized to validate such effectiveness
[29]. Regression of 95% gingivitis and suppuration in all the teeth irrigated with Brazilian
Green Propolis gel (BGPg), as well as a pocket depths and all treated patients with the BGPg
showed periodontitis/gingivitis regression. This result suggest that 10% BGPG used could be
used as an adjuvant therapeutic method assigned for the treatment of periodontal disease
(Figure 2) [142]. Ethanol Propolis Extract (EPE) inhibited all the Candida albicans strains
collected from HIV-seropositive and HIV-seronegative Brazilian patients with oral candidia‐
sis. No significant difference was observed between Nystatin and EPE. But significant
differences were observed between EPE and other antifungals. C. albicans showed resistance
to antifungal agents. This fact suggests commercial EPE could be an alternative medicine for
candidosis treatment from HIV-positive patients (Figure 3) [143]. Brazilian commercial ethanol
propolis extract, also formulated to ensure physical and chemical stability, was found to inhibit
oral candidiasis in 12 denture-bearing patients with prosthesis stomatitis candidiasis associa‐
tion is show in Table 12 and Figure 4 [144]. Also, denture stomatitis presents as a chronic disease
in denture-bearing patients, especially under maxillary prosthesis. Despite the existence of a
great number of antifungal agents, treatment failure is observed frequently. So, the clinical
efficacy of a Brazilian propolis gel formulation in patients diagnosed with denture stomatitis
was evaluated. Thirty complete-denture wearers with denture stomatitis were enrolled in this
pilot study. At baseline, clinical evaluation was performed by a single clinician and instructions
for denture hygiene provided. Fifteen patients received Daktarin® (Miconazole gel) and 15
received Brazilian propolis gel. All patients were recommended to apply the product four
times a day during one week. Clinical evaluation was repeated by the same clinician after
treatment. All patients treated with Brazilian propolis gel and Daktarin® had complete clinical
remission of palatal candidiasis edema and erythema. [77]. Noronha [31] found the efficacy of
a Brazilian green propolis mucoadhesive gel (BPGg) in preventing and treating the oral
mucositis and candidiasis in patients harboring malignant tumors and receiving radiotherapy.
All patients who used the gel applied 24 hours before the first radiotherapy session, three times
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a day, during the whole period(six weeks) of radiotherapy, did not develop mucositis and
candidosis over the entire period of radiotherapy.
Figure 2. Periodontitis treatment with mucoadhesive green propolis gel. A) Evidencing of dental plaque with basic
fuchsin. B) Confirmation of insertion loss and presence of periodontal pockets with periodontal probe. C) Applying
mucoadhesive green propolis gel intra-periodontal pocket. D) Clinical aspect of the periodontium after treatment
with gel containing propolis (Cairo do Amaral et al. [142].
The prevalence of candidosis in denture wearers is as well established as its treatment with
antifungal agents (AAs). However, little research has been done regarding the effects of AAs
on denture base surfaces. Then, da Silva et al.[150] evaluate the effects of fluconazole (FLU),
nystatin (NYS) and propolis orabase gel (PRO) on poly (methyl-methacrylate) (PMMA)
surfaces. So, PRO was able to induce changes in PMMA surface properties, such as roughness,
which could be related to microbial adhesion [146]. Recurrent aphthous stomatitis (RAS) is a
common, painful, and ulcerative disorder of the oral cavity of unknown etiology. No cure
exists and medications aim to reduce pain associated with ulcers through topical applications
or reduce outbreak frequency with systemic medications, many having serious side effects.
Propolis is a bee product used in some cultures as treatment for mouth ulcers. A randomized,
double-blind, placebo-controlled study, patients were assigned to take 500 mg of propolis or
a placebo capsule daily. Subjects reported a baseline ulcer frequency and were contacted
biweekly to record recurrences. Data were analyzed to determine if subjects had a decrease of
50% in outbreak frequency. The data indicated a statistically significant reduction of outbreaks
in the propolis group (Fisher's exact test, one sided, p = 0.04). Patients in the propolis group
also self-reported a significant improvement in their quality of life (p = 0.03). This study has
shown propolis to be effective in decreasing the number of recurrences and improve the quality
of life in patients who suffer from RAS [145].
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Figure 3. Inhibition zones of in vitro culture of Candida albicans collected from HIV-positive patients exposed to Etha‐
nol Propolis Extract (EPE= P), and antifungal agents: CL= clotrimazole; FL= fluconazole; EC= Econazole; NY =Nystatin;
AL= Alcohol; DW= Destiled water. (Martins et al., 2002) [143].
Figure 4. Clinical aspects of oral candidosis in patients with Total Removable Dental Prothesis (TRDP). A) Before prop‐
olis use. B) After propolis use. Source: Prof. Vagner Santos archives (2005) [146].
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Patient Age
(years) Race Gender Prosthesis Local lesions Antifungal
agent Result
ISS Hard 29 B F TRDP palate/soft palate Nys +
SVCL 34 W F TRDP Hard palate Nys +
AFF 36 W M TRDP Hard palate Nys +
GMR 37 W M TRDP Hard / soft palate Nys ++
MIC 39 B F TRDP Hard palate NYS +
AFS 71 B F TRDP Hard palate Nys ++
EGSM 29 W F TRDP Hard /soft palate EPE +
TMS 31 B F TRDP Hard palate EPE ++
LMC 33 W M TRDP Hard palate EPE +
HL 38 W M TRDP/PRDP Hard palate/ alveolar
mucosa EPE +
SFS 39 W F TRDP Hard /soft palate EPE ++
MCTS 43 W M TRDP/PRDP Hard palate/ alveolar
mucosa EPE +
MJNM 46 W F TRDP Hard palate EPE ++
46 B F TRDP Hard palate EPE +
HBS 48 B M TRDP Hard palate EPE +
JJAF 50 W F TRDP Hard palate EPE +
GRA 56 W F TRDP Hard palate EPE ++
NMBA 63 W F TRDP Hard palate EPE ++
Table 12. Clinical aspects of patients with oral candidiasis from Clinic of Semiology and Pathology of Dentistry School
UFMG participating in this study and Results of in vivo patients treatment of oral candidiasis with 20% Brazilian green
ethanol propolis extract (EPE) and Nystatin (Nys). Use posology: 4 time/day for 7 days, topic application in local lesion
and prosthesis surface F, female; M, male; TRDP, total removable dental prosthesis; PRDP, partial removable dental
prosthesis; B, black; W, white. (Santos et al., 2005) [146]
9. Future perspectives
The potential pharmacological activity investigation of natural products, especially antimi‐
crobial activity, has attracted the attention of several researchers. Increase of bacterial resist‐
ance to traditional antimicrobial agents and side effects are often seen [147, 28]. Many
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mouthwashes with alcohol are used as adjuvants in the control of dental plaque and gingivitis,
but undesirable side effects are observed, despite its efficacy. This stimulates the research of
alternative products, such as the use of toothpastes and mouthwashes based on natural
products, because there is the need for prevention and treatment options that are safe, effective
and economical. Mouthwash based on herbal extracts and propolis are for sale in the Brazilian
and world market, without, however, have undergone clinical studies proving their effective‐
ness and documenting possible undesirable side effects. Previous studies have demonstrated
the efficacy of propolis extracts as an antimicrobial agent useful for dental caries and perio‐
dontal pathogens microorganisms in in vitro studies [24,78,59,148,149]. Propolis standardiza‐
tion is necessary and several authors from different countries are involved in the study of
pharmacological activity and mechanism of action of various types of propolis. The separation
of organic compounds and their mechanism of action on cells may lead to new products that
can be important in controlling tumor growth, and infection control. However one should not
forget that the effect of synergism observed in raw propolis is responsible for its excellent
antimicrobial activity making it a unique product against bacterial and fungal resistance.
Moreover, pre-clinical and clinical phase I, II, III studies are necesssary in order to better
determine the effect on patients and safety. Several components of propolis have shown
efficacy in the growth inhibition of in vitro tumor cells and in vivo tumors. This may be the way
to the discovery of drugs against cancer, however, the clinical confirmations should be
prioritized. The diversity of pharmacological properties of propolis may also be extended to
studies against autoimmune diseases in order to ameliorate the clinical evolution. Also, studies
against systemic diseases that affect largely population world as is the case of diabetes and
hypertension. But for that attention should turn to as separation of compounds that can be a
great gain for treatment of these diseases.
(a)
(b)
Figure 5. (a) Physical aspect of Brazilian green crude propolis. (b) Plant caracteristic of Baccharis dracunculifolia. (Prof.
Vagner Santos archives, 2012).
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Propolis component Pharmacological properties Author/year
Green Propolis extract Apoptosis and cell propliferation Giertsen et al, 2011 [153]
Moronic acid Epstein-Barr virus suppresion Chang et al., 2010 [154]
Polyphenols Neurological diseases Farooqui and Farooqui, 2012 [15]
Red propolis extract Adipocyte differentiation Iio et al., 2010 [155]
Caffeic acid phenethyl ester
Cardanol, cardol
Antitumoral / anticancer,
citotoxicity
Chuu et al., 2012 [156]
Sawaya et al., 2011 [39]
Chan et al., 2012 [152]
Watanabe et al., 2011 [159]
Teerasripreecha et al, 2012 [68]
epicatechin, p-coumaric acid, morin, 3,4-
dimethoxycinnamic acid, naringenin, ferulic
acid, cinnamic acid, pinocembrin, and chrysin ,
3-prenyl-4-hydroxycinnamic acid
Antioxidant Guimaraes et al., 2012 [95]
Guo et al., 2011 [87]
Sawaya et al, 2011 [39]
3-prenyl-4-hydroxycunnamic acid, 2,2-
dimethyl-6-carboxyethenyl,2H-1-benzopyran;
3,5-diprenyl-4-hydroxycinnamic acid derivative
4 (DHCA4) 2,2-dimethyl-6-
carboxyethenyl-2H-1-benzopyran (DCBEN
Antiparasitic Trypanosoma cruzi;
Leishmania amazonensis
Sawaya et al., 2011 [39]
Salomao et al., 2008 [160]
Salaomao et al., 2011 [161]
Green, red and brown propolis extracts;
Artepillin C; Crysin
Anti-inflamatory Marcucci et al., 2000 [11]
Ha et al., 2010 [158]
Sawaya et al., 2011 [39]
Moura et al., 2011 [57]
Orsatti et al., 2012 [128]
Green, Red, Brown propolis extract; p-coumaric
acid (PCUM), 3-(4-hydroxy-3-(oxo-butenyl)-
phenylacrylic acid (DHCA1); Caffeic acid,
caffeoylquinic acid, diterpenic acids, flavonoids
antimicrobial Martins et al., 2002 [143]
Paula et al., 2006 [59];
Santos et al., 2007 [71]
Dias et al., 2012 [162];
Mattigatti et al., 2012 [163] Sawaya
et al., 2011 [39]
Choudhari et al., 2012 [157]
Table 13. Recent advances in propolis components studies.
Propolis: Alternative Medicine for the Treatment of Oral Microbial Diseases
http://dx.doi.org/10.5772/54003
155

(a)
(b)
Figure 6. (a) Physical aspect of Brazilian red propolis. (Prof. Vagner Santos archives, 2012) (b) Dalbergia ecastophylum
plant aspect. http://www.google.com.br/imgres?q=Dalbergia+ecastophyllum&num=10&hl=pt
BR&biw=1280&bih=673&tbm= isch&tbnid=WIUAFEd2jCOSxM:&imgrefurl=http://meliponariojandaira.blogspot.com/
2011/02/abelhas-indigenas-sem-ferrao.
Acknowledgements
Research Foundation of Minas Gerais State (FAPEMIG), National Council of Scientific and
Tecnologic Development (CNPq) for financial support in all of our research group and also
for supporting the publication of this chapter. Special thanks to Gustavo Araujo and Rafael
Tomaz.
Author details
Vagner Rodrigues Santos
Address all correspondence to: vegneer2003@yahoo.com.br
Universidade Federal de Minas Gerais, Faculty of Dentistry, Department of Clinical, Pathol‐
ogy and Surgery, Laboratory of Microbiology and Biomaterials, Brazil
Alternative Medicine
156

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