Oleocanthal, a Phenolic Derived from Virgin Olive Oil: A Review of the Beneficial Effects on Inflammatory Disease

Abstract

Virgin olive oil (VOO) is credited as being one of many healthful components of the Mediterranean diet. Mediterranean populations experience reduced incidence of chronic inflammatory disease states and VOO is readily consumed as part of an everyday dietary pattern. A phenolic compound contained in VOO, named oleocanthal, shares unique perceptual and anti-inflammatory characteristics with Ibuprofen. Over recent years oleocanthal has become a compound of interest in the search for naturally occurring compounds with pharmacological qualities. Subsequent to its discovery and identification, oleocanthal has been reported to exhibit various modes of action in reducing inflammatory related disease, including joint-degenerative disease, neuro-degenerative disease and specific cancers. Therefore, it is postulated that long term consumption of VOO containing oleocanthal may contribute to the health benefits associated with the Mediterranean dietary pattern. The following paper summarizes the current literature on oleocanthal, in terms of its sensory and pharmacological properties, and also discusses the beneficial, health promoting activities of oleocanthal, in the context of the molecular mechanisms within various models of disease.
Keywords: virgin olive oil; ibuprofen; sensory; inflammation; health

Full text

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This is the published version
Parkinson,L and Keast,R 2014, Oleocanthal, a phenolic derived from virgin
olive oil: a review of the beneficial effects on inflammatory disease,
International journal of molecular sciences, vol. 15, no. 7, pp. 12323-12334.
Available from Deakin Research Online
http://hdl.handle.net/10536/DRO/DU:30069038
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Reproduced with the kind permission of the copyright owner
Copyright: 2014, Multidisciplinary Digital Publishing Institute

Int. J. Mol. Sci. 2014, 15, 12323-12334; doi:10.3390/ijms150712323
International Journal of
Molecular Sciences
ISSN 1422-0067
www.mdpi.com/journal/ijms
Review
Oleocanthal, a Phenolic Derived from Virgin Olive Oil:
A Review of the Beneficial Effects on Inflammatory Disease
Lisa Parkinson and Russell Keast *
School of Exercise and Nutrition Sciences,
Centre of Physical Activity and Nutrition Research (CPAN), Deakin University,
221 Burwood Highway, Burwood, VIC 3125, Australia; E-Mail: ljlu@deakin.edu.au
* Author to whom correspondence should be addressed; E-Mail: russell.keast@deakin.edu.au;
Tel.: +61-3-9244-6944; Fax: +61-3-9244-6017.
Received: 27 May 2014; in revised form: 25 June 2014 / Accepted: 26 June 2014 /
Published: 11 July 2014
Abstract: Virgin olive oil (VOO) is credited as being one of many healthful components
of the Mediterranean diet. Mediterranean populations experience reduced incidence of
chronic inflammatory disease states and VOO is readily consumed as part of an everyday
dietary pattern. A phenolic compound contained in VOO, named oleocanthal, shares
unique perceptual and anti-inflammatory characteristics with Ibuprofen. Over recent years
oleocanthal has become a compound of interest in the search for naturally occurring
compounds with pharmacological qualities. Subsequent to its discovery and identification,
oleocanthal has been reported to exhibit various modes of action in reducing inflammatory
related disease, including joint-degenerative disease, neuro-degenerative disease and
specific cancers. Therefore, it is postulated that long term consumption of VOO containing
oleocanthal may contribute to the health benefits associated with the Mediterranean dietary
pattern. The following paper summarizes the current literature on oleocanthal, in terms of
its sensory and pharmacological properties, and also discusses the beneficial, health
promoting activities of oleocanthal, in the context of the molecular mechanisms within
various models of disease.
Keywords: virgin olive oil; ibuprofen; sensory; inflammation; health
OPEN ACCESS

Int. J. Mol. Sci. 2014, 15 12324
1. Introduction
The health promoting attributes associated with following a traditional Mediterranean diet have
been recognised for decades, with the first suggestion of healthful effects accompanying the Seven
Countries Study [1]. The risk of chronic inflammatory disease in Mediterranean populations are the
lowest in the world, and life expectancy amongst the highest [2] which has earned the populations
residing along the Mediterranean sea considerable attention from nutrition researchers worldwide.
Since the inaugural Seven Countries Study numerous other studies have supported the view that this
pattern of eating is associated with a reduced incidence of inflammatory disease states [3–11].
The principle source of dietary fat in the Mediterranean diet is virgin olive oil (VOO) [12] and this
has in part been recognised as a contributing factor towards the favourable health profile that the
Mediterranean population possess [13]. Throughout history VOO has been recognized as valuable
pharmacological agent in the hands of ancient Greek doctors [14]. Hippocrates mentions approximately
60 health conditions where VOO use can be beneficial, for example many skin conditions, wounds and
burns, amongst others. Typically traditional Mediterranean populations consume 25–30 mL of oil as
part of their diet, generally in salad dressings as well as cooked foods [15].
Importantly VOO contains approximately 36 phenolic compounds, and it is this minor phenolic
fraction of VOO that is partially responsible for the health benefits that accompany intake [16–18]. An
expanding volume of studies (including human, in vivo and in vitro) have reported that VOO phenolics
have beneficial effects on inflammation, antioxidant status, antimicrobial activity, as well as other
biological markers of non- communicable disease. (for review see [18]).
A phenolic compound in VOO that stands alone in terms of sensory and anti-inflammatory
attributes is decarboxy methyl ligstroside aglycone (also known as oleocanthal) [19]. Oleocanthal is
homologous with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen [19] for both
perceptual and anti-inflammatory properties. Both compounds produce a localised irritation in the
oropharangeal region and further research instigated, because of the perceptual similarities, found that
oleocanthal shares a similar anti-inflammatory action with Ibuprofen [19] therefore oleocanthal is now
acknowledged as a naturally occurring NSAID [20–24].
Importantly it has been proposed that the long term daily ingestion of virgin olive oil (containing
oleocanthal), which is a common attribute of the traditional Mediterranean diet, may be partially
responsible for the favorable health profile of Mediterranean populations [19]. Chronic low doses of
ibuprofen and other COX inhibitors such as aspirin have been shown to have anti-carcinogenic and
anti-thrombotic effects [25–27]. Therefore, it is plausible that low, chronic doses of a naturally
occurring NSAID such as oleocanthal may attenuate inflammation over time, and may then contribute
to significant reductions in the development of chronic inflammatory disease.
2. Oleocanthal Identification
Oleocanthal was first documented in literature as a phenolic compound contained in VOO in the
early 90’s [28]. It was a decade later that the compound, then known as decarboxy methyl ligstroside
aglycone, was suggested to be the sole phenolic responsible for the distinct throat irritation and
pungency elicited by some VOOs [29]. Beauchamp and colleagues, substantiated this finding over a

Int. J. Mol. Sci. 2014, 15 12325
decade later reporting that decarboxy methyl ligstroside aglycone was the sole irritant phenolic
responsible for the peppery stinging sensation experienced with VOO ingestion and aptly named the
compound oleocanthal (oleo for olive, canth for sting, and al for aldehyde) [19].
The confirmatory finding that oleocanthal is the sole irritating compound in VOO was achieved
by quantifying oleocanthal from various VOO’s and measuring the throat irritation accompanying
ingestion. However, to exclude the possibility that other compounds in VOO may also contribute to the
unique perceptual characteristic, oleocanthal was synthesised and dissolved in corn oil. The measure of
the throat irritation from the addition of oleocanthal to non-irritating corn oil was found to be dose
dependent on oleocanthal and mimicked the irritation of VOO [19] confirming that indeed oleocanthal
is the sole compound responsible for throat irritating sensation.
A point of interest is that the spatial irritation produced by oleocanthal is specific to the
oropharyngeal region. Generally irritant or pungent compounds are perceived in all regions in the oral
cavity, rather than isolated to a spatially distinct area. This implies that a sensory receptor specific to
oleocanthal exists in the oropharyngeal region [30]. Peyrot des Gachons and colleagues [31] have
identified the Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) as the
receptor linked to oleocanthal. This large inter-individual variation in sensitivity to oleocanthal may
then be due to variation in expression of TRPA1 receptors in the oropharyngeal region.
3. Sensory and Anti-Inflammatory Profile of Oleocanthal
A key characteristic of VOO quality is pungency and irritation. These attributes are recognised
as the positive reinforcement of VOO quality by those who frequently consume the oil, such as
Mediterranean populations. So much so, that prized VOO’s are rated as one cough or two cough oils,
with the latter classed as superior [31]. There is reported variation in the concentration of oleocanthal
contained in VOO. A recent study has reported that the concentration of oleocanthal contained in VOO
ranges from 284 to 711 mg/kg in a variety of Greek oils [32] and similar variance was also reported in
an earlier study [33].
Although the concentration of oleocanthal differs amongst oils and may influence irritant properties
of the oil [34], there is another key factor. The degree in which an individual experiences bitterness
or irritation of a compound is determined by an individual’s sensitivity to the compound, and large
inter-individual variation in the perceived intensity of irritation of oleocanthal has been reported.
Cicerale and colleagues [30] reported that intensity ratings of irritation to a oleocanthal concentration
of 54 mg/kg, contained in the VOO matrix, ranged from a slight irritation in the throat, to an irritation
that was of intensity sufficient to produce a cough in those highly sensitive.
Fischer and colleagues hypothesised that similar perceptual properties may be reflective of similar
pharmacological properties as early as 1965, suggesting that the more pronounced the perceptual
properties, the more potent the pharmacological properties [35]. For example, the more bitter tasting a
compound is rated, the more potent the anti-inflammatory, anti-oxidant, or anti-microbial actions of
that compound may be. This may have important implications for investigations into suitable naturally
occurring NSAIDs. If levels of TRPA-1 are expressed in a coordinated manner throughout the body,
and greater expression results in higher oropharyngeal irritation, then perhaps muscle and other tissue
would also have high expression levels of TRPA-1 receptor. To elaborate, oleocanthal sensitivity is

Int. J. Mol. Sci. 2014, 15 12326
linked to variation in oropharyngeal TRPA1 levels, and TRPA-1 is activated in response to inflammatory
cytokines. Therefore differences in oral sensitivity may indicate how oleocanthal influences inflammatory
pathways in muscle (Figure 1). Future investigations may determine if oleocanthal differentially
attenuates inflammation based on individual differences in perceptual sensitivity to the oropharyngeal
irritation elicited by this phenolic compound.
Figure 1. It is possible that receptor levels of TRPA-1 in muscle reflect levels in the
oropharyngeal region. Therefore low or high levels of TRPA-1 in the oropharyngeal region
may reflect the inflammatory responses in muscle through activation of P38 MAPK.
TRPA-1 recepto
r
Highly sensitive
TRPA-1 receptor
insensitive
Tissue
TRPA-1 receptor
P38
MAPK
Cytokine
promoters
Infla mmation
After the perceptual similarity between oleocanthal and ibuprofen were confirmed, Beauchamp
and colleagues [19] explored the possibility that the pathway of anti-inflammatory activity was
also analogous between compounds. The results of the study clearly show that oleocanthal inhibits
cyclooxygenase 1 and 2 (COX 1 & 2) enzymes in a dose-dependent manner, and does in fact mimic
the anti-inflammatory action of the synthetic NSAID ibuprofen. The important and novel findings of
Beauchamp and colleagues [19] demonstrate that oleocanthal not only mimics the mode of ibuprofen
inflammatory activity, but inhibits COX 1 and COX 2 enzymes significantly more at equimolar
concentrations. For example, oleocanthal (25 µM) inhibits 41%–57% of COX activity in comparison
to ibuprofen (25 µM) which inhibits 13%–18% of COX activity. This adds further weight to
oleocanthal as a potential factor in the health benefits associated with a traditional Mediterranean Diet.
Assuming approximately 70% absorption, then 50 mL/day corresponds to approximately 10% the current
Ibuprofen pain relieving dose. This estimate differs according to oleocanthal concentrations in VOO.

Int. J. Mol. Sci. 2014, 15 12327
4. Oleocanthal and Cancer
Numerous in vitro studies have reported that the phenolic compounds in VOO can inhibit the
initiation and metastasis of several types of cancer. This in turn supports the abundance of associative
evidence highlighting the lower incidence of many types of cancer, including breast, prostate, lung and
gastrointestinal cancer that are observed in Mediterranean populations when compared to Western
populations [36–40]. The inflammatory enzymes attenuated by oleocanthal, COX 1 and COX 2,
are responsible for the conversion of arachidonic acid to prostaglandins and thromboxane, which are
produced in response to inflammatory or toxic stimuli [41]. One cyclooxygenase enzyme, COX 2
is implicated in the pathogenesis of several cancers, in both human and animal studies [42–46].
Because oleocanthal is a naturally occurring COX inhibitor, it is becoming a compound of interest in
cancer research.
Recent evidence highlights oleocanthal as therapeutic medium by which monocyte chemoattractant
protein 1 (MIP-1α) is attenuated in a human multiple myeloma cell line (ARH-77). MIP-1α is reported
to be a critical instigator of malignant lesions in bone marrow milieu [47]. Additionally, Khanal and
colleagues [48] have recently demonstrated that oleocanthal exerts an anti-proliferative effect, and
therefore prevents tumour induced cell transformation in mouse epidermal JB6 Cl41cells. Oleocanthal
accomplishes this via the inhibition of extracellular signal-regulated kinases 1/2 and p90RSK
phosphorylation. Furthermore, oleocanthal encourages cell apoptosis by activating caspase-3 and
poly-adenosine diphosphate-ribose polymerase, phosphorylates p53 (Ser15), and also induces the
fragmentation of DNA in HT-29 cells derived from human colon adenocarcinoma [48]. In addition to
this it would seem from recent observations that oleocanthal potentially disrupts the pathogenesis of
c-Met kinase related malignancies. Elnagar and colleagues [22] have reported that oleocanthal has
significant anti-proliferative effects that have been demonstrated in both human breast and prostate
cancer lines. Additionally data from this study showed that oleocanthal exhibits anti-migratory and
anti-invasive actions in PC-3 and MDA-MB-231 cells possibly as a result of its ability to inhibit c-Met
phosphorylation [22].
Further to this, recent research has unveiled an unusual effect of oleocanthal on heat shock protein
90 (Hsp90) [49]. Hsp90 is a chaperone protein that stabilizes a number of proteins that are required
for tumor growth. Therefore Hsp90 inhibitors are investigated as anti-cancer drugs. Margarussi and
colleagues report that oleocanthal significantly reduce two Hsp90 proteins, Akt and Cdk4 without
actually influencing Hsp90 regulation in 2013. Furthermore oleocanthal had a pro-apoptotic effect on
cancer cells but only a slight effect on the viability of peripheral blood mononuclear cells, which is a
common attribute of Hsp90 inhibitors. It would therefore seem that oleocanthal may be a compound of
interest in regards to endeavours to identify a new class of Hsp90 inhibitors [49], and is a compound of
importance in future cancer research.
5. Oleocanthal and Joint-Degenerative Disease
Inflammation plays a significant role in the pathogenesis of joint degenerative disease and given the
prevalence of this disease it is important to identify suitable pharmacological interventions. Oleocanthal
has recently been highlighted as a therapeutic compound that may be of interest in the quest to find

Int. J. Mol. Sci. 2014, 15 12328
suitable natural NSAIDs for the treatment of joint degenerative disease. Pro-inflammatory cytokines
stimulate nitric oxide (NO) production [50], up-regulate the synthesis of cartilage degrading enzymes,
as well as increase prostaglandin PGE2 production, all factors that are implicated in the development
of joint-degenerative disease. In osteoarthritis (OA) pathogenesis, diseased cartilage synthesizes NO
spontaneously from diseased chrondocytes [51]. NO plays a pivotal role in joint-degenerative disease
and the stable end product of NO, nitrite (NO2), is significantly expressed in arthritic synovial fluid [20].
NO is biosynthesized by nitric oxide synthase (NOS). Another form of NOS is inducible NOS (iNOS)
which is primarily responsible for the inflammatory actions of NOS [52]. Iacano and colleagues reported
that oleocanthal and synthesized derivatives, attenuate production of iNOS protein expression in an LPS
challenged murine chondrocytes, in a dose dependent manner.
Also, as oleocanthal inhibits COX enzymes, and prostaglandins are downstream of COX then it is
possible that oleocanthal may also exert pharmacological actions in the treatment of both rheumatoid
arthritis and osteoarthritis through COX inhibition. COX enzymes are a catalyst for the formation of
prostaglandins and prostaglandins are highly expressed in the arthritic spine in an animal model [53].
Therefore, oleocanthal may attenuate arthritic pain through inhibition of prostaglandins, specifically
the synthesis of PGE2 that accompanies COX inhibition.
Inflammatory mediators such as Interleukin 6 (IL-6) and (MIP-1α) have been associated with
osteoarthritis (OA) and rheumatoid arthritis (RA) [54,55] and accordingly NSAIDs are often prescribed,
however with considerable adverse effects, such as damage to gastrointestinal mucosa [56]. Scotece
and colleagues (2012) investigated the effects of oleocanthal exert on potential targets of joint
inflammation reporting that oleocanthal inhibits NO production in J774 macrophages and inhibits both
IL-6 and MIP-1α in both ATDC5 chrondocytes and J774 macrophages [57]. These inflammatory
cytokines are both implicated in the inflammatory process and cartilage destruction of inflammatory
arthropathies. Further to this, oleocanthal decreased expression of other pro-inflammatory markers
Interleukin 1 (IL-1), tumour neurosis Factor (TNFα), and granulocyte-macrophage colony-stimulating
factor (GM-CFS). This study not only investigated the anti-inflammatory effects of oleocanthal
in chondrocytes but also macrophages which is relevant as synovial macrophages generate the
inflammatory cascade occurring in synovial fluid that leads to OA and RA [57]. Subsequently these
authors suggest that there is a justification for oleocanthal to be developed as a therapeutic agent for
future treatment of joint degenerative disease.
6. Oleocanthal and Brain Health
Ibuprofen has long been known to exert beneficial effects on markers of neuro-degenerative
disease [58], therefore it was seen as logical to investigate oleocanthal’s role as a natural
pharmacological agent, based on similarities between compounds in both perceptual and anti-inflammatory
properties. Li and colleagues [23] have presented important findings demonstrating that oleocanthal
inhibits tau fibrillization in vitro by forming an adduct with PHF6 peptide. PHF6, is a VQIXXK
motif that resides in the microtubule binding region [59]. Common lesions that are observed in
neuro-degenerative disease (i.e., Alzheimer’s disease) are hyperphosphorylated tangles of tau and the
PHF6 peptide enables the phosphorylation of tau. Therefore as oleocanthal modifies the PHF6 peptide
it then disturbs tau-tau interaction and the subsequent fibril formation. Motivated to discover the

Int. J. Mol. Sci. 2014, 15 12329
mechanism by which oleocanthal reacts with the tau protein Monti and colleagues [24] reported that
oleocanthal covalently modifies the construct of tau referred to as K18 in biologically relevant
conditions [24]. Oleocanthal cross linked with two lysine residues and the end result was the
rearrangement of the skeleton producing a more stable piridinium like complex [24].
Another type of lesion that are characteristic of Alzheimer’s disease are Β-amyloid peptides
(Aβ) [60]. Derived from Aβ are diffusible ligands (ADDLs) which are neurotoxic factors believed to
initiate the onset of Alzheimer’s disease [21]. In vitro evidence suggests that oleocanthal alters the
structure of ADDLs and augments antibody clearance of ADDLs, therefore protecting hippocampal
neurons from ADDL toxicity [21]. Of particular interest is the recent study conducted by Abuznait
and colleagues [61]. This study importantly reported both in vitro and in vivo data indicating that
oleocanthal enhances the clearance of Aβ by up regulating P-glycoprotein (P-gp) and also LDL
lipoprotein receptor related protein-1 (LRPI). The authors focused on two peptide species that have
been implicated in Alzheimer’s disease, both 1-Aβ40 and 1-Aβ42 mice brain endothelial cells. It was
concluded that oleocanthal significantly enhanced the clearance rate of 1-Aβ40 in these cells. Further to
that oleocanthal was tested for the first time in vivo. Intraperitoneal administration was conducted at
10 mg/kg/day of oleocanthal, twice daily over a duration of 2 weeks to wild type mice. Results showed
that after administration of oleocanthal, the clearance rate of 1-Aβ40 was enhanced and moreover
degradation of 1-Aβ40 was increased [61].
A recent cross sectional Australian study concluded that those suffering neurodegenerative disease
showed a significantly lower adherence to a Mediterranean style dietary pattern [62], and there is a
plethora of evidence research showing up to a 40% decrease in Alzheimer’s disease in populations
consuming a Mediterranean style diet [63]. Perhaps oleocanthal, in conjunction with other phenolics,
exerts a neuro-therapeutic potential that is reflected in the low incidence of neurodegenerative disease
in populations that regularly consume the oil.
7. Further Considerations
The bioavailability of a nutrient is an important consideration when discussing potential health
benefits. The bioavailability of the larger VOO phenolics, hydroxytyrosol, tyrosol and oleuropein has
been confirmed (for review see [17]). Only one study has investigated the bioavailability of oleocanthal
to date. Garcia-Villalba and colleagues [64] reported that largest concentration of metabolites produced
and found in human urine were from oleocanthal, as well as hydroxytyrosol and oleuropein. This
provides evidence of the metabolism of oleocanthal in the human body, however further studies are
required to achieve an in depth understanding of the metabolism and bioavailability of this compound.
There are limitations when discussing the pharmacological actions of compounds. Certainly there is
strong evidence that oleocanthal is an effective anti-inflammatory agent and demonstratespharmacological
actions in vitro. However future in vivo studies are necessary to fully elucidate the potential of this
compound as a pharmacological agent. There are many difficulties in extrapolating in vitro results to
in vivo and caution must be taken when reporting the effects of a compound removed from the matrix
in which it is normally contained. VOO phenolics function in a synergetic manner and complement
each other in terms of anti-inflammatory, anti-oxidant, and anti-microbial properties, therefore oleocanthal,
in addition to other VOO phenolics, plays a role in the health benefits associated with VOO intake.

Int. J. Mol. Sci. 2014, 15 12330
8. Conclusions
In summary, a diet reflecting that which is consumed by the Mediterranean populace, incorporating
daily VOO intake, has received significant attention over the last 40 plus years. Adherence to this
dietary pattern is associated with a positive health profile and it would seem that VOO has beneficial
effects on several health parameters. The phenolic fraction in particular has been highlighted to have
beneficial anti-inflammatory effects in several studies. Since its discovery oleocanthal, a VOO phenolic,
has gained a reputation of being a compound of interest in the goal of identifying therapeutic targets
against many chronic inflammatory disease states including cancer, neurodegenerative, and joint
degenerative disease. Oleocanthal efficiency in decreasing markers of arthritis, disrupting processes
vital to the formation of Alzheimer’s and being a neuro-protective compound in vitro is confirmed.
Furthermore oleocanthal reduces proliferation, migration and also promotes apoptosis in cancer cells
as well as preventing tumour induced cell transformation. Oleocanthal’s bioavailability in vivo is not
yet fully established, and this is important to access the pharmacological efficiency of oleocanthal.
While there are many limitations associated with focusing on a compound outside the food matrix in
which it is normally contained, it would seem that oleocanthal alone has significant pharmacological
properties in vitro and is becoming recognised as a potential therapeutic agent.
Acknowledgments
Funding for this study was provided by the School of Nutrition and Exercise Science,
Deakin University.
Author Contributions
Lisa Parkinson assessed the studies, extracted data and wrote the manuscript; Russell Keast
oversaw the writing of the manuscript draft, and both authors contributed to the final version.
Conflicts of Interest
The authors declare no conflict of interest.
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