Redox stress and brain functions

氧化还原应激和大脑功能

• 批准号: RGPIN-2018-06182
• 负责人: Ramassamy, Charles
• 金额: $ 2.11万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683225
• 关键词: Redox; stress; brain; functions

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.**

抗氧化剂是所有需氧生物控制活性氧 (ROS) 水平和氧化应激诱导毒性的基础。然而，抗氧化剂的作用不仅限于其氧化还原活性，因为它们还可以调节应激反应途径（Nrf2、NF-κB）和蛋白质磷酸化。人们还普遍认识到，脂质氧化的副产物可以调节信号转导途径。我的研究计划的长期目标是了解氧化应激和抗氧化剂系统对大脑功能和体内平衡的基本作用。***抗氧化剂不稳定，容易氧化，生物利用度和吸收率低，导致其生物效应降低。为了克服这一缺点，我们在纳米科学或自然科学领域开发了一项新的研究计划，通过设计生物相容性和可生物降解的纳米粒子（NP）来保持和提高其生物利用度和功效。因此，这里介绍的计划是一项正在进行的计划，具有长期愿景，旨在增强靶向纳米粒子的抗氧化剂从血液到大脑的输送。为此，我们设计了带有或不带有聚乙二醇（PEG）的***聚乳酸乙交酯酸（PLGA）或聚乳酸（PLA）纳米颗粒来封装抗氧化剂，并研究了它们对神经元功能的影响。我们发现将姜黄素负载到 PLGA-NP 中可以增加其神经元摄取、抗氧化和神经保护活性。姜黄素是一种食品成分，也是一种强大的抗氧化剂。我们的初步数据强化了这样的概念：聚合物成分和涂层的性质对于负载抗氧化剂的纳米颗粒的神经元效应至关重要。这些结果引起了人们的极大兴趣，因为 PLGA-NP 和 PLA-NP 是用于脑靶向和药物递送的有前景的纳米载体。最近的进展为当前提案中概述的研究目标奠定了基础。然而，大脑通过血脑屏障与血流分开，血脑屏障由非常特殊的内皮细胞代表。这些细胞和纳米粒子之间的相互作用仍有待记录。 ***我们假设纳米颗粒与血脑屏障 (BBB) 之间相互作用的每一步（内吞作用、转胞吞作用、细胞效应）及其生物分布都需要纳米颗粒具有不同且最佳的理化特性。因此，对于当前的提案，我们的具体目标是：（1）合成和表征生物相容性和可生物降解的纳米颗粒库； (2)分析BBB内皮细胞对这些纳米粒子的内吞、转胞吞作用及其对细胞氧化还原电位的影响以及载脂蛋白的影响； (3) 研究这些纳米颗粒在斑马鱼和小鼠模型中的生物分布。***我们相信，这样一个全面的研究计划将为我们开发用于脑靶向的纳米颗粒的长期目标提供肥沃的土壤。**