NEUROPROTECTIVE AND ANTI-INFLAMMATORY PROPERTIES OF HYDROXYTYROSOL: A PROMISING BIOACTIVE COMPONENT OF WINE

Abstract

Hydroxytyrosol (HT) is a phenolic compound present in olives, virgin olive oil and wine. HT has attracted great scientific interest due to its biological activities which have been related with the ortho-dihydroxy conformation in the aromatic ring. In white and red wines, HT has been detected at concentrations ranging from 0.28 to 9.6 mg/L and its occurrence has been closely related with yeast metabolism of aromatic amino acids by Ehrlich pathway during alcoholic fermentation. One of the most promising properties of this compound is the neuroprotective activity against pathological mechanisms related with neurodegenerative disorders including Alzheimer’s and Parkinson’s disease. Alpha-synuclein (αsyn), is a 140 amino acid protein abundant in the brain. In Parkinson’s disease, insoluble forms of this protein accumulate forming inclusions termed Lewy bodies which unravel different molecular events that finally cause the death of dopaminergic neurons. In order to evaluate the capacity of HT to inhibit αsyn fibril formation and to study the effect of this compound against αsyn induced toxicity and inflammation, several techniques have been used including fluorescence spectroscopy, transmission electronic microscopy, RT-PCR, western blot and immunohistochemistry. Our results demonstrate that HT (at micromolar levels, 25-50 µM) presents a strong inhibitory effect preventing not only αsyn aggregation but also exercising a destabilising effect by disaggregating αsyn fibrils. Moreover, HT is able to counteract αsyn-induced toxicity totally reverting the death of neuronal cells (PC12 cell line). Additionally, HT can reduce inflammation induced by αsyn fibrils in microglial cells (BV2 cell line). Indeed, a reduction of mRNA levels of TNF-α, iNOS, IL-1β, IL-6 and CXCL10 was observed after the co-treatment of BV2 with HT and αsyn fibrils. Our results also demonstrated that the molecular mechanisms involved in this effect are related with the modulation of mitogen activated protein kinases (MAPKs) and the generation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. To sum up, our data support the use of HT to prevent neurotoxicity and inflammation associated with Parkinson’s disease.