Abstract
Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68® (P68) and dequalinium (DQA) which have suitable characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood–brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood–brain barrier (BBB) passage of HT by 50% (p < 0.0001, n = 6). This resulted in increased protection against rotenone induced cytotoxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments (p < 0.01, n = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD-related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models.
Highlights
Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD)
The aim of this study was firstly to assess the ability of the Pluronic F68® (P68) + DQA micellar nanocarriers to incorporate HT, alone or in combination with DFO, and secondly to assess whether these nanoformulations could protect against reduced cell viability and increased oxidative stress induced by a rotenone model of PD in a hCMEC/D3-SHSY5Y Transwell® co-culture system
20 μM HT and 20 μM HT + 100 μM DFO pre-treatments. This perhaps relates to the reported iron chelating properties of HT [83], suggesting that there may be little added value in combining HT and DFO, despite the combination treatments being the most effective overall. These results suggest that P68 + DQA HT and HT + DFO nanocarriers have the relevant characteristics to access the brain without producing cytotoxicity and protect against rotenone induced oxidative stress
Summary
Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD). The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood–brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). Animal studies have shown resistance to oxidative stress via reduced lipid peroxidation in dissociated brain cells following administration of published maps and institutional affiliations
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