Hydroxytyrosol and dopamine metabolites: Anti-aggregative effect and neuroprotective activity against α-synuclein-induced toxicity

The abnormal aggregation of the alpha-synuclein (alpha syn) protein is involved in the formation of Lewy bodies in the brain of patients suffering from Parkinson disease (PD). Hydroxytyrosol (HT), a polyphenolic compound present in olives, olive oil, and wine, has been shown to inhibit aggregation and destabilise the alpha syn aggregates, pre-venting neuronal cell death. However, very limited data have been published on the study of its metabolites. Therefore, this study investigated the capacity of the metabolites 3,4-dihydroxyphenylacetaldehyde (DOPAL), 4-hydroxy-3-methoxyphenylethanol (MOPET), and 3-methoxy-4-hydroxyphenylacetaldehyde (MOPAL) to prevent the aggregation and toxic effects of alpha syn fibrils. In vitro techniques, such as Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis, thiazolyl blue tetrazolium bromide (MTT), and Real-Time PCR (RT-PCR) were used. Our results show that among these three metabolites, DOPAL exerts the greatest effect, preventing aggregation and alpha syn-induced neurotoxicity. In fact, DOPAL has the ability to completely inhibit alpha syn fibril formation at low doses. Moreover, this metabolite has a potent destabilising effect on the alpha syn fibrils. Concerning neuroprotection, DOPAL can counteract the toxicity induced by alpha syn. The vitagene expression results show a possible relationship between the neuroprotection mechanism exhibited by DOPAL and the modulation of SIRT-2 and Hsp70.