Antioxidant nanoconjugates and neurodegenerative diseases

Abstract

Gold nanoparticles (GNPs) are becoming a promising platform for the delivery of drugs in the treatment of Oxidative Stress (OS), which is considered the key modulator in Neurodegenerative Diseases (ND). This thesis explores the hypothesis that the nanodelivery of Lipoic Acid (LA), a powerful antioxidant, can be an effective strategy against the OS in ND. In the first part of this thesis, I synthesize and characterise the antioxidant nanoconjugate system GNPs-LA and an oxidant system based on GNPs and the aggregates of α-Synuclein, the protein involved in the pathogenesis of ND, in particular Parkinson’s Diseases (PD). I then explore the effect of the antioxidant and oxidant nanoconjugate systems on SH-SY5Y cells, a human neuronal cell model widely used to study ND. In doing so, I first examine the in vitro cytotoxicity of the nanoconjugates trying to highlight the benefits that a drug delivery system can bring in comparison to the use of free molecules. I show that the nanoconjugate systems nicely internalise within the cellular compartments before looking further at the role of both the oxidant GNPs-α-Synuclein and the antioxidant GNPs-LA in ROS generation. I show that the former is baneful for the cells as it is efficient in increasing lipid membrane peroxidation, whilst this decreases with the exposure of the cells to the latter. The beneficial effect of GNPs-LA is also confirmed by the outcomes of biochemical assays employed to monitor the mitochondrial respiratory function and the level of glutathione within the cells. Finally, this thesis moves on the study of the role of the two gold nanoconjugates on both biophysical behaviour and structural changes in the cytoskeleton of the cells. I show that GNPs-LA have a protective role on both, suggesting that an interplay exists between ROS, mitochondrial respiratory function and cell structure. In conclusion, lipoic acid-nanoconjugates display antioxidant effects, so protecting the cells against OS induced by α-Synuclein aggregates in ND.