OLEUROPEIN

The beneficial effects of oleuropein Oleuropein is the main polyphenol present in the leaves and fruits of the olive tree; it is found in extra virgin olive oil both in the form linked to a glucose molecule (glycated) and in the non-glycated form. For some time, natural polyphenols have attracted growing interest for their beneficial properties against numerous diseases, ranging from cancer to cardiovascular diseases, diabetes, neurodegenerative diseases and, more generally, for their ability to counteract the aging of cells, tissues and the whole organism. These properties are not limited to their known antioxidant power but go far beyond; the most recent studies have begun to demonstrate the effective clinical efficacy of the administration of polyphenols on humans and to reveal the molecular and cellular mechanisms with which these substances exert these effects and which are the basis of the nutritional virtues commonly associated with the so-called “Mediterranean Diet ”.

The results of the clinical trials conducted, together with the available epidemiological and experimental data consistently support the protective effect associated with the daily intake of oleuropein through the use of nutraceutical preparations consisting of olive leaf extracts enriched with the substance. 

The data provided by scientific research are particularly significant as regards the anti-neurodegenerative and anti-diabetic effects of oleuropein. The former were reported thanks to a series of studies carried out both on neuronal cells in culture and on model animals, in particular genetically modified mice in order to mimic a brain situation similar to that present in Alzheimer’s disease, the main form of dementia associated to aging in humans. In these mice, the administration of oleuropein with the normal meal in doses equivalent to approximately 200-°©-300 mg in humans has clearly beneficial effects in terms of cognitive performance, which are maintained at levels comparable with those of normal mice of the same age . At the histopathological and cellular level, this effect can be traced back to the reduction of the load of amyloid plaques (which characterize the disease) and of the inflammatory response and, in parallel, to a strong stimulation of the autophagic response, which protects the cell against the toxicity of the plaques and stimulates its reabsorption. These effects, which show a clear dose-°©-dependence, are similar to those produced by other polyphenols (resveratrol, curcumin, epigallocatechins) and can, at least in part, be traced back to the mobilization of calcium from intracellular deposits with the consequent activation of signals that result in the activation of autophagy. It has also been demonstrated that oleuropein can directly reduce the load of amyloid plaques by favoring a pathway that reduces the production of the precursor peptide of the same. Furthermore, recent studies on other polyphenols demonstrate effects of an epigenetic type, consisting in the modulation of the expression of particular sets of genes following reversible chemical modifications of the chromatin which do not alter the genetic heritage but the way in which it is expressed. These studies explain the anticancer effects of these polyphenols and, presumably, also those exerted by oleuropein, through the regulation of the activity of enzymes involved in the chemical modifications of chromatin.

 The antidiabetic action of oleuropein is supported by recent clinical trials. One of these showed that the daily administration of about 50 mg of the polyphenol for 12 weeks to a group of middle-aged, overweight subjects at risk for developing type 2 diabetes reduced blood sugar and improved both the secretion and insulin sensitivity. Another study conducted in human subjects with type 2 diabetes given 500 mg of oleuropein per day for 14 weeks showed a significant improvement in glucose homeostasis, with reductions in glycosylated hemoglobin and fasting insulin levels, while a reduction in starch digestion and absorption was noted in rats treated with oleuropein. Other studies have shown that in vitro oleuropein prevents the amyloid aggregation of amylin, a peptide secreted together with insulin by pancreatic beta cells, the aggregates of which are believed to be co-responsible for the cellular suffering that accompanies the onset of diabetes type 2. The efficacy of oleuropein in contrasting both the onset of type 2 diabetes and some of its consequences can be seen in a broader protective effect against the metabolic syndrome. In fact, other studies have shown that in mice, oleuropein attenuates fatty liver disease and reduces obesity induced by a high-fat diet. The anti-°©-obesity effect and the modulation of glucose homeostasis had previously been reported also for other plant polyphenols. In conclusion, the available scientific data convincingly support the efficacy of the daily intake of large doses of oleuropein for the prevention of pathologies linked to aging such as senile dementia and cancer, or to metabolic disorders such as type 2 diabetes and the metabolic syndrome. The constant daily intake of large doses of oleuropein through the supplementation, with nutraceutical products, of the normal content of the substance in the diet therefore appears useful and recommendable in order to prevent and treat the metabolic syndrome and type 2 diabetes mellitus, also in consideration of the absence of side effects related to the intake of oleuropein. 

Bibliography

• Phenols and Polyphenols from Argania spinosa. Z. Charrouf and D. Guillaume, American Journal of Food Technology, 2007, 2, pages 679-683, 
• Prossnitz, Eric R.; Barton, Matthias (2014). “Estrogen biology: New insights into GPER function and clinical opportunities”. Molecular and Cellular Endocrinology 389 (1-2): 71–83. 
• Haris Omar, Syed (2010). “Oleuropein in Olive and its Pharmacological Effects”. Scientia Pharmaceutica 78 (2): 133–54. 
• Sudjana, Aurelia N.; D’Orazio, Carla; Ryan, Vanessa; Rasool, Nooshin; Ng, Justin; Islam, Nabilah; Riley, Thomas V.; Hammer, Katherine A. (2009). “Antimicrobial activity of commercial Olea europaea (olive) leaf extract”. International Journal of Antimicrobial Agents 33 (5): 461–3. 
• Barbaro, Barbara; Toietta, Gabriele; Maggio, Roberta; Arciello, Mario; Tarocchi, Mirko; Galli, Andrea; Balsano, Clara (2014). “Effects of the olive-derived polyphenol oleuropein on human health”. International Journal of Molecular Sciences 15 (10): 18508–18524. 
• Tripoli, Elisa; Giammanco, Marco; Tabacchi, Garden; Di Majo, Danila; Giammanco, Santo; La Guardia, Maurizio (2009). “The phenolic compounds of olive oil: Structure, biological activity and beneficial effects on human health”. Nutrition Research Reviews 18 (1): 98–112. 
• Walter Jr, WM; Fleming, HP; Etchells, JL (1973). “Preparation of antimicrobial compounds by hydrolysis of oleuropein from green olives”. Applied microbiology 26 (5): 773–6. 
• Andreadou, Ioanna; Iliodromitis, Efstathios K.; Mikros, Emmanuel; Constantinou, Maria; Agalias, Apostolos; Magiatis, Prokopios; Skaltsounis, Alexios Leandros; Kamber, Elli; et al. (2006). “The Olive Constituent Oleuropein Exhibits Anti-Ischemic, Antioxidative, and Hypolipidemic Effects in Anesthetized Rabbits”. The Journal of Nutrition 136 (8): 2213–9. 
• Leehuang, S; Huang, P; Zhang, D; Lee, J; Bao, J; Sun, Y; Chang, Y; Zhang, J; Huang, P (2007). “Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition”. Biochemical and Biophysical Research Communications 354 (4): 872–8. 
• Lee-Huang S, Huang P, Huang P (July 11–16, 2004). “Anti-HIV activity of olive leaf extract and synergism with HAART”. Int Conf AIDS 15th. Bangkok.
• Leri M, Natalello A, Bruzzone E, Stefani M, Bucciantini M. Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-42 aggregation. Food Chem Toxicol. 2019 Apr 14. pii: S0278-6915(19)30214-5. 
• Palazzi L, Bruzzone E, Bisello G, Leri M, Stefani M, Bucciantini M, Polverino de Laureto P.  Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates.  Sci Rep. 2018 May 29;8(1):8337.     
• Miceli C, Santin Y, Manzella N, Coppini R, Berti A, Stefani M, Parini A, Mialet-Perez J, Nediani C.  Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB.  Oxid Med Cell Longev. 2018 Mar 26;2018:8067592.     
• Nardiello P, Pantano D, Lapucci A, Stefani M, Casamenti F.  Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-β Deposition.  J Alzheimers Dis. 2018;63(3):1161-1172.     
• Leri M, Oropesa-Nuñez R, Canale C, Raimondi S, Giorgetti S, Bruzzone E, Bellotti V, Stefani M, Bucciantini M.  Oleuropein aglycone: A polyphenol with different targets against amyloid toxicity.  Biochim Biophys Acta Gen Subj. 2018 Jun;1862(6):1432-1442.     
• Casamenti F, Stefani M.  Olive polyphenols: new promising agents to combat aging-associated neurodegeneration.  Expert Rev Neurother. 2017 Apr;17(4):345-358.     
• Luccarini I, Pantano D, Nardiello P, Cavone L, Lapucci A, Miceli C, Nediani C, Berti A, Stefani M, Casamenti F.  The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study.  J Alzheimers Dis. 2016 Sep 6;54(2):737-50.     
• Rigacci S, Stefani M.  Nutraceutical Properties of Olive Oil Polyphenols. An Itinerary from Cultured Cells through Animal Models to Humans.  Int J Mol Sci. 2016 May 31;17(6). pii: E843.     
• Pantano D, Luccarini I, Nardiello P, Servili M, Stefani M, Casamenti F.  Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology.  Br J Clin Pharmacol. 2017 Jan;83(1):54-62.     
• Leri M, Nosi D, Natalello A, Porcari R, Ramazzotti M, Chiti F, Bellotti V, Doglia SM, Stefani M, Bucciantini M.  The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies.  J Nutr Biochem. 2016 Apr;30:153-66.     
• Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, Nardiello P, Luccarini I, Casamenti F, Stefani M.  Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.  Oncotarget. 2015 Nov 3;6(34):35344-57.     
• Casamenti F, Grossi C, Rigacci S, Pantano D, Luccarini I, Stefani M.  Oleuropein Aglycone: A Possible Drug against Degenerative Conditions. In Vivo Evidence of its Effectiveness against Alzheimer’s Disease.  J Alzheimers Dis. 2015;45(3):679-88.     
• Rigacci S, Stefani M.  Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols.  Expert Rev Neurother. 2015 Jan;15(1):41-52.     
• Luccarini I, Grossi C, Rigacci S, Coppi E, Pugliese AM, Pantano D, la Marca G, Ed Dami T, Berti A, Stefani M, Casamenti F.  Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates.  Neurobiol Aging. 2015 Feb;36(2):648-63.     
• Luccarini I, Ed Dami T, Grossi C, Rigacci S, Stefani M, Casamenti F.  Oleuropein aglycone counteracts Aβ42 toxicity in the rat brain.  Neurosci Lett. 2014 Jan 13;558:67-72.     
• Grossi C, Ed Dami T, Rigacci S, Stefani M, Luccarini I, Casamenti F.  Employing Alzheimer disease animal models for translational research: focus on dietary components.  Neurodegener Dis. 2014;13(2-3):131-4.     
• Grossi C, Rigacci S, Ambrosini S, Ed Dami T, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M.  The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.  PLoS One. 2013 Aug 8;8(8):e71702.     
• Diomede L, Rigacci S, Romeo M, Stefani M, Salmona M.  Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.  PLoS One. 2013;8(3):e58893.     
• Rigacci S, Guidotti V, Bucciantini M, Nichino D, Relini A, Berti A, Stefani M.  Aβ(1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon.  Curr Alzheimer Res. 2011 Dec;8(8):841-52.    
• Rigacci S, Guidotti V, Bucciantini M, Parri M, Nediani C, Cerbai E, Stefani M, Berti A.  Oleuropein aglycon prevents cytotoxic amyloid aggregation of human amylin.  J Nutr Biochem. 2010 Aug;21(8):726-35.