Oleacein it is a phenolic compound which derives from the transformation of oleuropein, a glucoside belonging to the family of secoiridoids, present in all parts of the olive tree, but in higher concentrations in young olives and leaves.
During the extraction of the oil, in particular the malaxation, the oleuropein undergoes the deglycosylation , demethylation enzymatic, biochemical transformations that lead to the formation of theoleacein.
Chemically, oleacein is the dialdehyde form of decarboxy-methyl-elenolic acid linked to hydroxytyrosol, also known as 3,4-DHPEA-EDA, which under certain conditions can separate into two components: hydroxytyrosol and elenolic acid.
Oleacein is an ester of hydroxytyrosol but, unlike this, which is water-soluble, That è amphipathic (or amphiphilic), that is, it dissolves in both water and fats.
Thanks to the property amphipathic and antioxidant, can integrate into blood low-density lipoproteins (LDL), offering, once incorporated, a protective shield against oxidation (LDLox), counteracting the formation of arterial plaque.
Oleacein was identified for the first time in 1993 by Montedoro G. et al. and by Scalzo RL et al. while in 1996 Hansen, following a studio on hypotensive properties of olive leaf extracts, something already known since ancient times, coined the name (1).
Hansen attributed the term to this secoiridoid “oleacein”, as derived from “Olea”, in reference to the plant, "ACE”, to the biological action on theEenzyme of Cconversion of theAangiotensin I ed “INA” from inhibitor.
The main pharmacological actions of ACE inhibitors (including drugs) are vasodilation, increased sodium excretion, diuresis and lowering blood pressure.
Furthermore i macrophages, immune cells with the role of "scavengers of the human body", play a fundamental role in all phases of the inflammatory process, in response to external stimuli, when activated by microbial endotoxins or inflammatory cytokines. In this case, the expression of the enzyme iNOS (Inducible Isoform of Nitroxide Synthase) increases, which produces nitric oxide (NO) e citrulline, starting from the amino acid L-arginine.
NO is a signaling molecule with many physiological functions, but, when produced in high amounts, it plays a key role in the pathogenesis of inflammation.
Therefore, compounds with the ability to decrease NO levels in stimulated macrophages, such as oleacein, are considered anti-inflammatory molecules.
Oleacein reduces the amount of L-citrulline and nitric oxide generated by macrophages stimulated by bacterial toxins, in a dose-dependent manner, in a concentration range between 12,5 and 25 µM.
(I remind you that the oleacein content in EVO oil is very variable: from 11,5 mg/kg obtained from the Koroneiki cultivar and 253,9 mg/kg from the Coratina variety) (2).
Another property of oleacein is that of inhibit the “coupled enzyme system” with cyclooxygenase (COX-1 and COX-2) and of the 5-lipoxygenase (5-LOX).
Both of these two groups of enzymes act in inflammatory states, after phospholipase-2 (PLA-2), released thearachidonic acid from the fatty acids of the phospholipids of cell membranes, thus allowing the initiation of arachidonic acid cascade which leads to the formation of inflammatory molecules such as leukotrienes (via 5-LOX), i thromboxanes and prostaglandins (via COX-1).
5-LOX is an enzyme that synthesizes leukotrienes as inflammatory mediators, starting from arachidonic acid; excessive activity of this enzyme is associated with pathological conditions such as asthma, arthritis, inflammatory bowel disease, and some chronic diseases.
Therefore, in inflammatory conditions, there is an increase in the production of prostaglandins from the COX street and the leukotrienes from the 5-Lipoxygenase pathway.
Until recently, only its anti-inflammatory action was known of oleocanthal, another biophenol of the oil, for its action similar to ibuprofen, Farmaco Aanti-inflammatory nOn-Stheroid (NSAIDs), both capable of inhibiting cyclooxygenase COX-1.
Oleacein shows an inhibitory activity on the COX-2 enzyme, 13 times greater than oleocanthal, although its inhibitory activity on COX-1 is an order of magnitude lower.
Nonsteroidal anti-inflammatory drugs, such as ibuprofen, usually cause damage to the gastric mucosa due to the inhibition of COX-1, since the prostaglandins produced by this enzyme, in the gastric epithelium, act as cytoprotective agents (3, 4).
Therefore, it was thought that selective COX-2 inhibitors would have lower gastrointestinal toxicity. But these inhibitors were found to be responsible for cardiotoxicity and cardiovascular events because, by blocking the COX-2 pathway, metabolism is altered, exacerbating the COX-1 and 5-LOX pathways, lowering the prostacyclin (PGI2) which acts as a vasodilator, relaxing the smooth muscles of blood vessels and as an inhibitor of platelet aggregation, preventing the formation of clots.
Furthermore, PGI2 also plays a role in the immune system, with predominantly anti-inflammatory or immunosuppressive effects.
Compounds that act on single molecular targets have been shown to produce toxicity and unwanted activity, while compounds that act on multiple targets simultaneously produce a better therapeutic profile.
Therefore, the dual LOX/COX inhibition of oleacein, has been recommended as a desirable approach in the development of new anti-inflammatory drugs (5)
Some compounds, such as darbufelone and lycofelone, had already been designed and used clinically as COX/5-LOX dual pathway inhibitors; however, due to high toxicity and/or limited efficacy, they were not marketed.
Since it is known that natural products are potentially safer and more active than synthetic compounds, compounds from olive oil may be potential inflammation-inhibiting molecules.
Consequently, oleacein has been shown to be a “multi-target” drug, able to decrease the production of NO by macrophages stimulated by bacterial lipopolysaccharides and inhibit key enzymes of the arachidonic acid cascade, including PLA-2, 5-LOX, COX-1, and COX-2.
Furthermore, the physiological metabolites of oleacein, namely hydroxytyrosol and hydroxytyrosol sulfate-acetate, show anti-inflammatory properties found in cellular systems; in this way, the metabolism in vivo of oleacein increases the anti-inflammatory activity.
Some groups are exploring the neuroprotective potential of oleacein and this molecule has demonstrated an agonist action on the TrkB receptor, promoting the expression of brain-derived neurotrophic factor, a key protein involved in neuroplasticity (6). Other studies have demonstrated the potential effects of oleacein on promoting neurogenesis and on the mitigation of neuroinflammation is vitro and in vivo (7)
The results presented in numerous works broaden the knowledge on the anti-inflammatory activity associated with olive oil biophenols and suggest important clues for the development of new anti-inflammatory drugs based on these natural compounds (8).
Bibliography
1) Hansen K et al. Phytomedicine,1996; 2(4) 319-25.
2) Berti U. PM Active-Italy. 08/01/2022; https://active-italia.com/it/oleacein-from-italian-cultivar-coratina/
3) Arora M. et al. Life Sci. 2020, 251, 117631.
4) Jaismy Jacob P. et al. Eur. J. Pharm. Skiing. 2018, 121, 356–81.
5) Macedo T. et al. J. Ethnopharmacol. 2021, 269, 113746.
6) By Paolo Deandreis OliveOilTime, 28 / 06 / 2025
7) Wakasugi D. et al. Cell Communication and Signaling. 2024; 22, Art 309.
8) Costa V. et al. Biomedicines 2022,10(11), 2990.
