**5. Sensory properties of oleocanthal**

The intake of EVOO is often associated with a peppery sting that is localized to the oropharyngeal region in the oral cavity (Figure 3). There is wide inter-individual variation in sensitivity to oleocanthal which can range from a slight irritation in the throat, to an irritation that is strong enough to produce a cough in those highly sensitive. Of particular

Oleocanthal: A Naturally Occurring Anti-Inflammatory Agent in Virgin Olive Oil 361

prostaglandins and thromboxane which are produced in response to inflammatory or toxic stimuli. COX 1 and COX 2 can be harmful to the body. In particular, COX 2 has been implicated in the pathogenesis of several cancers in both human and animal studies (Harris et al., 2003, Boland et al., 2004, Subbaramaiah et al., 2002, Ristimäki et al., 2002), and may also play a role in atherosclerosis (Chenevard et al., 2003). The novel findings presented by Beauchamp and colleagues (Beauchamp et al., 2005) demonstrate that oleocanthal not only mimics the mode of ibuprofen action, it exhibits increased potency (compared with ibuprofen) in inhibiting COX 1 and COX 2 enzymes at equimolar concentrations. For instance, oleocanthal (25 µM) inhibited 41-57% of COX activity in comparison to ibuprofen

Moreover, Beauchamp and colleagues (Beauchamp et al., 2005) put forth the suggestion that chronic ingestion of small quantities of oleocanthal via EVOO consumption, may be responsible, in part, for the lowered prevalence of disease associated with the Mediterranean diet. Thus, if an olive oil consumer ingests around 50 g of EVOO a day containing approximately 200 μg/kg of oleocanthal, the person would ingest approximately 10 mg/day of oleocanthal. This would equate to a relatively low (10%) equivalent dose of ibuprofen (recommended for adult pain relief). Chronic low doses of ibuprofen and other COX inhibitors such as aspirin are known to have important health benefits in the prevention of cancer development (e.g. colon and breast) (Garcia-Rodriguez and Huerta-Alvarez, 2001, Harris et al., 2006) and CVD (Hennekens, 2002). Therefore, long term ingestion of oleocanthal via EVOO consumption may contribute to a reduction in chronic

Finally, it is important to note oleocanthal's bioavailability within the body. Only one study has investigated this to date. A study by Garcia-Villalba et al. (Garcia-Villalba et al., 2010) noted that oleocanthal was readily metabolized however further studies are required to gain a more thorough understanding of the metabolism and bioavailability of this compound.

Ibuprofen is known to exert beneficial effects on markers of neuro-degenerative disease (Van Dam et al., 2008) and based on the similar oral irritant properties and shared antiinflammatory mode of action via COX inhibition, oleocanthal was investigated for potential neuro-protective properties. Li and collegues (Li et al., 2009) presented significant findings demonstrating that oleocanthal inhibits tau fibrillization *in vitro* by forming an adduct with PHF6 peptide, which is a VQIXXK motif that resides in the microtubule binding region, and is crucial in the formation of tau fibrils (Li and Virginia, 2006) Hyperphosphorylated tangles of tau are lesions that are observed in neuro-degenerative disease (i.e. Alzheimer's disease) and PHF6 enables the phosphorylation of tau, thus the convalent modification of PHF6 peptide disrupts tau-tau interaction and subsequent fibril formation (Li et al., 2009) (Figure 4). Β-amyloid peptides (Aβ) are another type of lesion that are characteristic of Alzheimer's disease (Guela et al., 1998), as Aβ derived diffusible ligands (ADDLs) are neurotoxic factors proposed to instigate the onset of Alzheimer's disease (Pitt et al., 2009). Pitt and colleagues (2009) demonstrated that *in vitro*, oleocanthal alters the structure of ADDLs and augments antibody clearance of ADDLs, therefore protecting hippocampal neurons from ADDL toxicity. This data supports research showing a 40% decrease in Alzheimer's disease in

disease development and certainly emerging evidence supports this notion.

populations consuming a Mediterranean style diet (Scarmeas et al., 2009).

(25 µM) which inhibited only 13-18% of COX activity.

**6.1 Oleocanthal and neuro-degenerative disease** 

interest is the spatial location of irritation produced by oleocanthal. Irritating, pungent compounds often aggravate all regions in the oral cavity rather than acting on one localized area (Peyrot des Gachons et al., 2011), which implies a sensory receptor specific to oleocanthal exists in the oropharyngeal region of the oral cavity. Recent investigations have indeed verified that the TRPA1 is the receptor linked to oleocanthal and the anatomical location of this receptor has been found in the oropharyngeal region of the oral cavity (Peyrot des Gachons et al., 2011).

Fig. 3. Oleocanthal irritation occurs solely in the oropharyngeal region (area shaded in black) of the oral cavity.

A large variability among subjects in the perceived irritation from oleocanthal has been noted (Cicerale et al., 2009a). Such individual variation in perception of oleocanthal may be related directly to the quantity of the TRPA1 receptor, as has been reported for other oral stimuli such as the bitter compounds: 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC) (Hansen et al., 2006), which activate the TAS2R38 bitter receptor (Hayes et al., 2011). The important link between the perceptual aspects of oleocanthal and health benefits is the notion that variation in sensitivity to oleocanthal irritation may relate to potential differences in sensitivity to the anti-inflammatory action of this compound. However, further research is required to investigate this.
