Oleocanthal

Journal of Neurochemistry, 2009, 110(4):1339-1351.

Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau.[Reference: WebLink]

Tau is a microtubule-associated protein that promotes microtubule assembly and stability. In Alzheimer's disease and related tauopathies, tau fibrillizes and aggregates into neurofibrillary tangles. Recently, Oleocanthal isolated from extra virgin olive oil was found to display non-steroidal anti-inflammatory activity similar to ibuprofen. As our unpublished data indicates an inhibitory effect of Oleocanthal on amyloid beta peptide fibrillization, we reasoned that it might inhibit tau fibrillization as well.
METHODS AND RESULTS:
Herein, we demonstrate that Oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state. Using PHF6 consisting of the amino acid residues VQIVYK, a hexapeptide within the third repeat of tau that is essential for fibrillization, we show that Oleocanthal forms an adduct with the lysine via initial Schiff base formation. Structure and function studies demonstrate that the two aldehyde groups of Oleocanthal are required for the inhibitory activity. These two aldehyde groups show certain specificity when titrated with free lysine and Oleocanthal does not significantly affect the normal function of tau.
CONCLUSIONS:
These findings provide a potential scheme for the development of novel therapies for neurodegenerative tauopathies.

Arthritis & Rheumatology, 2010, 62(6):1675-1682.

Effect of oleocanthal and its derivatives on inflammatory response induced by lipopolysaccharide in a murine chondrocyte cell line.[Reference: WebLink]

In joint diseases, cartilage homeostasis is disrupted by mechanisms that are driven by combinations of biologic factors that vary according to the disease process. In osteoarthritis (OA), biomechanical stimuli predominate, with up-regulation of both catabolic and anabolic factors. Likewise, OA progression is characterized by increased nitric oxide (NO) production, which has been associated with cartilage degradation. Given the relevance of cartilage degenerative diseases in our society, the development of a novel pharmacologic intervention is a critically important public health goal. Recently, Oleocanthal isolated from extra virgin olive oil was found to display nonsteroidal antiinflammatory drug activity similar to that of ibuprofen, a drug widely used in the therapeutic management of joint inflammatory diseases. We undertook this study to evaluate the effect of Oleocanthal and its derivatives on the modulation of NO production in chondrocytes.
METHODS AND RESULTS:
Cultured ATDC-5 chondrocytes were tested with different doses of Oleocanthal and its derivatives. Cell viability was evaluated using the MTT assay. Nitrite accumulation was determined in culture supernatant using the Griess reaction. Inducible NO synthase (NOS2) protein expression was examined using Western blotting analysis. Oleocanthal and its derivatives decreased lipopolysaccharide-induced NOS2 synthesis in chondrocytes without significantly affecting cell viability at lower concentrations. Among the derivatives we examined, derivative 231 was the most interesting, since its inhibitory effect on NOS2 was devoid of cytotoxicity even at higher concentrations.
CONCLUSIONS:
This class of molecules shows potential as a therapeutic weapon for the treatment of inflammatory degenerative joint diseases.

Life Sciences, 2012,91(23–24):1229-1235.

Further evidence for the anti-inflammatory activity of oleocanthal: Inhibition of MIP-1α and IL-6 in J774 macrophages and in ATDC5 chondrocytes.[Reference: WebLink]

Given the relevance of degenerative joint diseases in our society, the development of a novel pharmacologic intervention is a critically important public health goal. Recently, Oleocanthal, a polyphenolic natural compound from extra virgin olive oil, has emerged as a potential therapeutic weapon for the treatment of inflammatory degenerative diseases. The goal of this study was to further evaluate the anti-inflammatory activity of Oleocanthal in murine macrophages J774 and murine chondrocytes ATDC5 with a particular focus on the inhibition of gene expression of pro-inflammatory factors such as MIP-1α and IL-6.
METHODS AND RESULTS:
ATDC5 murine chondrogenic cells and murine macrophages J774 were used. J774 macrophages were tested with different doses of Oleocanthal and cell viability was evaluated using the MTT assay. Western blot analysis was carried on in J774 cells using anti NOS2 antibody. Nitrite accumulation was determined in culture supernatant using the Griess reaction. MIP-1α and IL-6 mRNA levels were determined using SYBR Green-based quantitative RT-PCR. MIP-1α and IL-6 protein levels were evaluated using specific ELISA assay. Several cytokines, involved in the inflammatory response, were also tested by BioPlex assay. First, Oleocanthal inhibits LPS-induced NO production in J774 macrophages, without affecting cell viability. Moreover, it inhibits MIP-1α and IL-6 mRNA expression, as well as protein synthesis, in both ATDC5 chondrocytes and J774 macrophages. Oleocanthal also inhibits IL-1β, TNF-α and GM-CSF protein synthesis from LPS-stimulated macrophages.
CONCLUSIONS:
Our data confirm a clear potent role of Oleocanthal as anti-inflammatory therapeutic agent for future treatment of arthritis or other inflammatory diseases.