Received: March 19, 2007 J. Venom. Anim. Toxins incl. Trop. Dis.

Accepted: May 7, 2007 V.13, n.4, p.697-710, 2007.

Abstract published online: May 8, 2007 Review article.
Full paper published online: November 30, 2007 ISSN 1678-9199.

PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING ACTIONS

RAMOS A. F. N. (1), MIRANDA J. L. (1)

(1) Laboratory of Pathology, Department of Basic Sciences, Federal University of

Jequitinhonha and Mucuri Valleys, Minas Gerais State, Brazil.

ABSTRACT: Tissue healing is an adaptive biological response by which the

organism repairs damaged tissue. The initial stage of healing is represented by an
acute inflammatory reaction, in which inflammatory cells migrate to damaged tissue
and phagocyte debris. At a later stage, fibroblasts and endothelial cells proliferate
and generate a scar. The occurrence of inflammatory processes and healing
imperfections have been a concern for hundreds of years, especially for individuals
with healing difficulties, such as diabetics and carriers of peripheral circulation
deficiencies. A wide variety of natural products have been used as anti-inflammatory
and healing agents, with propolis being a remarkable option. Propolis has been used
in popular medicine for a very long time; however, it is not a drug intended for all
diseases. Currently, the determination of quality standards of propolis-containing
products is a major problem due to their varying pharmacological activities and
chemical compositions. The aim of this review is to discuss the use of propolis with
emphasis on its anti-inflammatory and healing properties.

KEY WORDS: propolis, inflammation, anti-inflammatory action, healing properties,

Apis mellifera.

CONFLICTS OF INTEREST: There is no conflict.

CORRESPONDENCE TO:
JOÃO LUIZ DE MIRANDA, Laboratório de Patologia, Universidade Federal dos
Vales do Jequitinhonha e Mucuri, Rua da Glória, 187, Centro, 39.100-000,
Diamantina, Minas Gerais, Brasil. Email: [email protected].
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 698

Propolis is a resinous substance with varying colors and consistencies, collected by

Apis mellifera bees from several vegetal sources. The word propolis comes from the
Greek pro meaning ‘in defense of’ and polis ‘city’, i.e. defense of beehives (3). In fact,
bees use propolis to protect themselves from insects and microorganisms, employing
it as a cement to seal cracks or open spaces in the hive, to sterilize the queen-bee
posture site, and to mummify insect invaders. Commonly, small animals or parts of
them are found wrapped within propolis in perfect states of conservation (23).
Propolis is a honeybee product with a very complex chemical composition, made by
gummy and balsamic material collected by bees from sprouts, flower-buds, trees and
other vegetal-tissue resinous exudates. During propolis collection, bees mix the
beeswax and the collected propolis with the 13-glicosidase enzyme found in their
saliva, hydrolyzing flavonoids glycosides into flavonoid aglycones (34). Afterwards,
the collected material is augmented with enzymatic and salivary secretions.
Along with other honeybee products (honey, royal jelly, pollen), propolis has
outstanding therapeutic properties (5), being used since 300 years B.C. in popular
medicine in various parts of the world. However, interest in the correlation of propolis
chemical composition with its pharmacological activities started only forty years ago
(23). In Brazil, little is known about propolis, and only few studies have been
conducted. Nonetheless, it is widely used in popular medicine. Propolis is one of the
few “natural drugs” being used for a long time by different civilizations (7). Currently,
several propolis products are being commercialized worldwide, including candies,
chocolate bars, shampoos, skin lotions, antiseptic mixtures, and toothpastes (1). The
Persians, Greeks, Romans and Incas also used propolis with therapeutic purposes.
In ancient Egypt, it was employed to embalm the dead, while in the Balkans States
propolis is widely used. In France, the term propolis is found in the general literature
since the sixteenth century. In South Africa, during the Anglo-Boer War, more than
90 years ago, it was used with vaseline for ointment preparation to heal war wounds.
This helped save the lives of many soldiers, since antibiotics were not yet available
(10). In the Second World War, Soviet medical clinics studied propolis with excellent
results.
The color of propolis depends on its origin. It varies from dark-brown to reddish-
brown, with a greenish tone. It has a typical odor, which can vary from sample to
sample, with some being odorless. Flashing point ranges between 60 and 70°C and,
in some cases, may reach up to 100°C. Generally, ethanol is the best solvent for
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 699

propolis preparation, and other solvents such as ethyl ether, water, methanol and
chloroform may also be used for extraction and identification of propolis compounds
(24). In addition, glycerin, propylene glycol, and other solutions have been used
during propolis preparation for pharmaceutical and cosmetic industries (46). Propolis
obtained from beehives, also known as rude propolis, is composed of around 50%
balsam resin, 30% wax, 10% essential and aromatic oils, 5% pollen, and 5% other
substances, including wood fragments (31).
The resin found in propolis is collected in vegetation nearby beehives, where bees
also collect pollen and nectar for feeding. Propolis composition is mainly determined
by the phytogeographic characteristics of beehive surroundings (19). However,
seasonal variation may occur within the same place (39). Also, variation was
observed among samples collected in the same place, but by different A. mellifera
subspecies (40). Several contaminants close by beehives can be collected and
unexpectedly added to propolis, such as asphalt powder, pesticide, iron excess,
copper, magnesium, (12) and even lead (2).
It is known that bees are selective when collecting resin from a specific vegetal
source, but factors that guide them are not completely understood (37, 45). The
nature of aromatic and terpene compounds found in propolis has a biological
importance, allowing bees to determine which vegetal species to visit (23).
The pharmacological activities of propolis are more numerous in tropical regions than
in temperate climates, reproducing the richer vegetal diversity observed in the former
(4, 28).
More than 300 different compounds have been identified so far in propolis, including
aliphatic acids, esters, aromatic acids, fatty acids, carbohydrates, aldehydes, amino
acids, ketones, chalcones, dihydrochalcones, terpenoids, vitamins, and inorganic
substances (23). Of all, flavonoids are the ones which draw greater research interest
(15).
Propolis has several therapeutic properties, such as antibacterial, anti-inflammatory,
healing, anesthetic (13), anticariogenic (34), antifungal, antiprotozoan and antiviral
activities. The in vitro antibacterial activity was verified against several Gram-positive
and Gram-negative bacteria and results from synergism between propolis
compounds, mainly pinocembrin and galangin flavonoids. Other flavonoids, such as
chrysin and kaempferol, have shown antiviral activity with reduction of intracellular
proliferation of some viruses, such as herpes simplex (23).
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 700

Many other biological and pharmacological properties of propolis have been noted:
cartilage, bone, and dental pulp regeneration; immunological properties; liver defense
and antitoxic activity; antioxidant and immunomodulatory actions. Consequently,
there has been increasing interest on propolis, with the chemical industry searching
for viable commercial formulations. Also, investigation of isolated compounds, such
as flavonoids, has grown. These compounds are biologically more active and are
responsible for propolis’ spasmodic (quercetin, kaempferol and pectolinarigenin),
anti-inflammatory (acacetin) and antiulcerative (apigenin) activities (11).
Propolis is a low-cost potential anti-inflammatory agent for both acute and chronic
stages (6). Its properties are used mainly for muscles and articulations, and also
other types of inflammations, infections, rheumatisms and torsions. Mice and rabbit
studies have shown that hydroalcoholic solutions of propolis possess anti-
inflammatory activity following topical, injectable, or even oral administration (23).
Inflammation is the complex biological response of vascular tissues to harmful stimuli
such as cell damage by pathogens. It is a protective attempt by the organism to
remove the injurious stimuli and to initiate the healing process. The tissue
modifications induced by the causal agent are responsible for the release of
inflammatory mediators that lead to subsequent inflammatory events. Cytokine
release (IL-1, TNF-α) by activated macrophages leads to vessel dilation and results
in smooth muscle relaxation and increased local blood flow (hypothermia).
Microvascular changes associated with increased vascular permeability take place,
leading to accentuated plasmatic exudation, phagocyte accumulation (neutrophils,
monocytes, macrophages), and amplification of endogenous chemical mediators.
Simultaneously, mast cells, phagocytic cells and endothelial cells use plasma
membrane lipids to generate important inflammatory mediators (21). In an
immediately posterior stage, several intra and extracellular phospholipases are
activated by cytoplasmic membrane phospholipids and activate other enzymes, such
as cyclooxygenase (COX) and lipoxygenase (LOX), which in turn act upon
arachidonic acid and eicosanoid metabolism, creating important inflammatory
mediators (prostaglandins and leukotrienes). These mediators are responsible for the
maintenance of the inflammatory process. The fibrinolytic system, kinins,
complement, vasoactive amines (histamine and serotonin), and nitric oxide (NO) may
lead to inflammation when physiologically altered (47).
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 701

Endothelial-leukocyte cellular adhesion occurs in a sequence of events, and specific

molecules are expressed in different stages. Selectins (E, P, and L), integrins (VLA-4
and LFA-1), and members of immunoglobulin super-families (ICAM-1 and ICAM-2)
transfer leukocytes from the vascular lumen into the tissues (35). In response to
several mediators, the vascular endothelium expresses specific glycoproteins on the
cell surface, which mediates blood leukocyte connection and extravasation, an
important event in tissue repair (3).
According to the frequency and duration of the injurious agent, the inflammatory
process can be classified into acute and chronic. The acute-stage response involves
serous, fibrinous, suppurative or exudative events as well as microvascular and
cellular events; this response to phlogogen occurs within 72h. The chronic stage
response includes proliferative events and histological alterations different from those
in the acute stage, being characterized by cell emigration and intensive mitosis.
Formation of giant multinuclear cells takes place, and all these events are induced by
phlogogen (42).
In certain instances, inflammation must be regulated by using specific drugs, since it
may lead to toxic consequences to the organism. The damage to the organism
during the inflammatory response is induced by free radicals produced by active
macrophages and neutrophils. These molecules degrade lipid acids of the plasma
membrane, disrupt membrane proteins, and induce DNA mutations. NO is another
potent inflammatory mediator produced by endothelial and inflammatory cells that
can induce tissue damage if synthesized in large quantities (21).
Some anti-inflammatory substances found in propolis have been isolated. According
to Mirzoeva & Calder (29), these substances are caffeic acid, quercetin, naringenin,
and caffeic acid phenethyl ester (CAPE). These compounds contribute to the
suppression of prostaglandins and leukotrienes synthesis by macrophages and have
inhibitory effects on myeloperoxidase activity, NADPH-oxidase, ornithine
decarboxylase and tyrosine-protein-kinase (30). Krol et al. (18) attributed propolis
anti-inflammatory activity to other compounds, including salicylic acid, apigenin,
ferulic acid and galangin.
It is known that macrophages are involved in several body physiology processes,
such as phagocytosis, enzyme release, free radical generation, and inflammation.
Scheller et al. (38) suggested that propolis immunostimulant activity may be
associated with macrophage activation and enhancement of macrophage phagocytic
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 702

capacity. The results of the study of Orsi et al. (33) corroborated the findings of
Schelle, which indicated that macrophages produce high amounts of H2O2.
While investigating the effects of individual propolis compounds complexes on lysine,
Ivanovska et al. (17) found that cinnamic acid tends to inhibit H2O2 release by
peritoneal macrophages, whereas caffeic acid induces increased metabolite
production.
The inhibition of NO production by macrophages may also be responsible for propolis
anti-inflammatory activity (32). Hu et al. (16) evaluated the anti-inflammatory effects
of ethanol (EEP) and water (WSD) extracts in ICR mice and Wistar rats on thoracic
capillary vessel leakage, carrageenan-induced edema, carrageenan-induced
pleurisy, acute lung damage, and Freund’s complete adjuvant (FCA)-induced
arthritis. In the experiment, EEP and WSD inhibited the increase of PGE2 and also
had a significant inhibitory effect on NO in carrageenan-induced pleurisy exudation.
In these models, NO could accelerate an inflammatory reaction by enlarging blood
vessels and causing edema. This could increase the expression of inflammatory
reactions and accelerate the development of blood poisoning by activating
prostaglandin synthesis, as seen in the progression of rheumatism. However, other
studies indicated increased NO production by macrophages (32).
Although the mechanism of WSD and EEP on anti-inflammatory performance was
apparently similar, there were some differences. In the carrageenan-induced pleurisy
and oleic-acid plus LPS-induced acute lung damage studies, WSD not only inhibited
the increase of white blood cells (WBC) count, but also inhibited the increase of
neutrophils (but not significantly at 5%). This would explain how WSD inhibits WBC
and alleviates inflammatory reactions during acute inflammation. The results suggest
that additional propolis components, other than flavonoids, possess anti-inflammatory
effects. Although EEP did not significantly inhibit WBC, it may possibly alleviate the
inflammatory degree synergistically by inhibiting NO. The arthritic rat model induced
by FCA is associated with an immune inflammation reaction in these experiments.
The main feature of rheumatoid arthritis (RA) is the ongoing damage in arthrosis of
cartilage and bone, in addition to a disturbance of the immune function. Cytokines
secreted by immune cells (lymphocyte and mononuclear-macrophage), fibroblasts,
and endothelial cells play an important role in immune and inflammatory responses in
vivo. The results of the present experiment show that EEP and WSD had significant
inhibitory effects on the levels of IL-6 in FCA-induced arthritis rats, but not on IFN and
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 703

IL-2 levels. This could also mean that, in the course of the anti-inflammatory activity
of WSD and EEP, the humoral immune system plays an important role inhibiting the
activation and differentiation of mononuclear macrophages. This would be a possible
mechanism for the anti-inflammatory and immune effects of WSD and EEP (16).
Inflammation can also be related to free radicals increase in the human organism (9).
Although oxidative damage is known to be involved in inflammatory-mediated tissue
destruction, modulation of oxygen-free radicals production represents a new
approach to the treatment of inflammatory diseases (8). Propolis contains
polyphenols and a wide range of other compounds capable of removing excessive
free radicals from our organism (25). CAPE, a flavonoid-like compound, has been
identified as one of the main active ingredients of honeybee propolis and has
antioxidant and anti-inflammatory properties (8). For that reason, Celik et al. (8)
investigated the efficiency of CAPE administration in preventing oxidative damage
due to Escherichia coli-induced pyelonephritis (PYN) in rats. The main hypothesis of
events leading to renal scarring has been that bacterial products (e.g.
lipopolysaccharide) stimulate the release of proinflammatory cytokines, which initiate
an inflammatory response, including chemotaxis with consequent extravasation of
polymorphonuclear leukocytes (PNL) (8). PNL release toxic products (e.g. free-
oxygen radicals and lysozymes) that seem to be responsible for tissue damage;
inhibition of the PNL-produced free radicals can greatly neutralize tissue damage
(14).
The levels of lipid peroxidation and NO production, and the activities of superoxide
dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) in E.
coli-induced PYN were evaluated in a rat model using kidney homogenates and were
significantly increased. However, CAPE administration reduced malondialdehyde
(MDA) levels, which is an indicator of free radical generation that increases in final
stages of lipid peroxidation. NO levels have been implicated in the mechanisms of
cell injury and long-term physiological changes in cellular excitability. This effect may
be due to decreased expression of inducible NO (iNOS) (14). In a similar study, Song
et al. (41) demonstrated that CAPE was able to inhibit iNOS expression and NO
production in macrophages. CAPE significantly increased the activities of the
antioxidant enzymes SOD and GSH-Px in the kidneys of infected rats. CAPE
administration significantly inhibited the activity of XO, a physiological source of
superoxide anions in eukaryotic cells. Histopathologic examination showed that
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 704

CAPE reduced inflammation induced by E. coli. In summary, CAPE administration

decreases the oxidative damage occurring in PYN and thus could be used for
medical management of bacterial nephropathy.
The effects of CAPE on cyclooxygenase-2 (COX-2) expression in Harvey-ras-
transformed WB-F344 rat live epithelial cells (H-ras WB cells) have also been
studied. Several reports have shown that activation of Ras signaling pathways is
involved in the induction of COX-2 and matrix metalloproteinase expression. COX
catalyzes the critical conversion of arachidonic acid into prostaglandins, which are
important mediators of the inflammatory process. Improper up-regulation of COX-2 is
relevant to the pathophysiology of inflammatory disorders. The eukaryotic
transcription factor nuclear factor kB (NF-kB) plays a central role in general
inflammatory as well as immune responses. The 5'-flanking region of the COX-2
promoter contains NF-kB binding sites. In agreement with this concept, NF-kB has
been shown to be a critical regulator of COX-2 expression in many cell lines (43).
CAPE significantly inhibited the constitutive expression of COX-2 and several studies
suggest that CAPE is a potent and specific inhibitor of NF-kB activation. In those
studies, histopathological examinations showed that CAPE significantly suppressed
inflammation. CAPE has been demonstrated to specifically and completely block the
activation of NF-kB induced by a wide variety of inflammatory agents, including TNF
and H2O2. The activation of NF-kB proteins is induced by many factors, such as
inflammatory cytokines (IL-1, TNF), bacterial products, and oxidative stress. Others
have shown that CAPE not only inhibits transcription factors, but also reduces the
production of IL-8 and monocyte chemotactic protein (20).
All the above-mentioned data have demonstrated different mechanisms of
inflammatory inhibition of several propolis preparations or its isolated compounds.
Nevertheless, the anti-inflammatory effects of propolis depend mainly on the
administration mode and dosage (29).
A wide variety of natural products have been used in wounds treatment due to their
easy application, innocuity, low cost, and bactericidal/bacteriostatic effect (26).
Propolis is remarkably used in dermatology for wounds healing, burn and external
ulcers treatment, healing time reduction, wound contraction increase, and tissue
repair acceleration. During wound healing, perfect synchronized cellular and
molecular interactions occur to repair damaged tissue (22). Healing is a dynamic
process involving harmonious biochemical and physiological stages, such as
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ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 705

inflammation, fibroblastic and tissue maturation. The wound healing process can be
summarized using the healing of a linear skin wound as a prototype. With any
wound, the initial events at the site of injury are hemorrhage and formation of a fibrin-
rich clot. Fibronectin stabilizes the clot before dehydration takes place and a scab is
formed. Macrophages soon follow neutrophils to the site of tissue injury and wound
debridement is aided by the opsonization of tissue by fibronectin. The epidermal
response to wounding is initiated very rapidly and within a day or so “tongues” of
epidermal cells can be seen cleaving a path between the scab and the viable
collagenous tissue underneath; two or three days after injury, the wound floor is
covered by a sheet of regenerated epidermal cells. The formation of granulation
tissue begins at about the same time with an influx and proliferation of fibroblasts and
the beginnings of new capillary formation. Four to five days after wounding,
stratification of the wound-floor epidermis is readily apparent, fibroblasts are highly
active and secretion of extracellular matrix compounds (especially GAGs and type III
collagen) and the process of neovascularization are in full swing. To achieve this
invasive process, endothelial cells must secrete a battery of proteinases (e.g. type IV
collagenase, interstitial collagenase, elastase, stromelysin, and plasminogen
activators) to degrade the basement membrane. The diverse components of the
epidermis are restored without the reformation of rete ridges, much of the type III
collagen fibers orient parallel to lines of mechanical stress (collagen remodeling), and
the once highly vascular granulation tissue undergoes a protracted process of
vascularization as it matures into relatively avascular scar tissue (27). Sutta et al. (44)
used propolis alcoholic solutions at animal wounds treatment in clinical and also
experimental cases. Histologically, they observed that propolis treatment induced
better healing by reducing the inflammatory response; consequently, epithelial
healing was faster with propolis. The authors considered propolis suitable for wound
treatment, following elimination of the infection. It is known that healing is directly
related to the inflammatory process (36), and if the latter is less pronounced,
production of healing molecules and deposition of collagen fiber bundles increase. It
is possible that prolonged inflammation unleashes pronounced necrosis, causing
more tissue damage and rendering the healing process more difficult. Propolis tissue
regeneration properties, including healing, are possibly due to its antioxidant activity.
Whenever free radicals are produced, they hamper or even block cells regeneration.
A. F. N. Ramos and J. L. Miranda. PROPOLIS: A REVIEW OF ITS ANTI-INFLAMMATORY AND HEALING
ACTIONS. J. Venom. Anim. Toxins incl. Trop. Dis., 2007, 13, 4, p. 706

Removal of free radicals by propolis flavonoids would allow regeneration of an ill

organ or tissue in an ordinary way (23).
The occurrence of the inflammatory process, along with imperfections in healing, has
been a problem for centuries. Despite advances on anti-inflammatory, antibiotic and
healing treatment, infections continue to be a major reason of concern, especially for
individuals that present difficulties in healing, such as diabetics and peripheral
circulation deficiency carriers.
It should be stressed that propolis is not a drug for all diseases. A major challenge
currently is the determination of which types of propolis are indicated for which
medical use, the appropriate dosages, and what effects propolis has on humans and
animals, since product quality varies widely. Several researchers have proposed
biological assays as well as quantitative analyses of chemical compounds from
different propolis samples. Quality-control problems have been confirmed in
countries where propolis is commercialized. Hypersensitivity responses induced by
propolis, especially those derived from cinnamic acid, have been reported; in the
future, an old question will have to be answered: which propolis is best suited for
which disease? Therefore, propolis’ precise pharmacological properties must be
determined. With further research and knowledge, development of new drugs will
become possible.

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