Redox stress and brain functions

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Antioxidants are fundamental for all aerobic organisms to control the levels of reactive oxygen species (ROS) and of oxidative stress induced-toxicity. However, the role of antioxidants is not only limited to their redox activity because they can also regulate stress response pathways (Nrf2, NF-?B) and protein phosphorylation. It is also well recognized that by-product of lipids oxidation can modulate signal transduction pathways. The long-term goal of my research program aims to understand the fundamental role of oxidative stress and antioxidants systems on brain functions and homeostasis.***Antioxidants are unstable, easily oxidized with low bioavailability and absorption, causing a reduction of their biological effect. To overcome this drawback, we have developed a new research program, in nanoscience or natural sciences, to preserve and increase their bioavailability and efficacy by engineering biocompatible and biodegradable nanoparticles (NPs). Thus, the program presents here is an ongoing program with long term vision to enhance the blood-to-brain delivery of antioxidants with targeted NPs. For this, we have engineered ***poly(lactic-co-glycolide acid) (PLGA) or polylactic acid (PLA) NPs with or without poly(ethylene glycol) (PEG) to encapsulate antioxidants and studied their effects on neuronal functions. We found that curcumin-loaded into PLGA-NPs increase its neuronal uptake, antioxidant and neuroprotective activity. Curcumin is a food ingredient and a powerful antioxidant. Our preliminary data strengthened the concept that the polymer composition and the nature of the coating is crucial for the neuronal effect of antioxidant loaded-NPs. These results are of great interest since PLGA-NPs and PLA-NPs are promising nanocarriers for brain targeting and drug delivery. This recent progress provides the foundation for the research objectives outlined in the current proposal. However, the brain is separated from the blood stream by the BBB which is represented by very specialized endothelial cells. The interaction between these cells and the NPs remain to be documented. ***We hypothesize that each step of interaction between NPs and the blood brain barrier (BBB) (endocystosis, transcytosis, cellular effects) and their biodistribution require different and optimal physico-chemical properties of NPs. Therefore, for this current proposal, our specific aims are: (1) To synthesize and characterize of a library of biocompatible and biodegradable NPs; (2) To analyze the endocytosis, transcytosis of these NPs by the endothelial cells of the BBB, their effects on the cellular redox potential and the impact of apolipoproteins; (3) To study the biodistribution of these NPs in zebrafish and in mouse models.***We are confident that such a comprehensive research program will provide a fertile ground for our long term goals for the development of NPs for brain targeting.**