MRI可示踪的木犀草素纳米复合物通过调控BDNF/NF-κB炎症通路治疗AD的作用研究

Alzheimer's disease (AD) is a common degenerative disease of the central nervous system and currently without cure. Increasing number of studies focus on treating AD with natural botanicals. We previously found that Luteolin could reduce LPS-induced pro-inflammatory cytokine release from BV2 cells. We also found that Luteolin could significantly alleviate the inflammatory response and increase the level of brain-derived neurotrophic factor (BDNF) in the brain of AD mice, and further improve the cognitive ability of the mice. However, natural botanicals show poor bioavailability and limited ability to cross the blood-brain barrier (BBB). We have previously successfully synthesized drug-loaded nanoparticles and verified their high efficiency into the brain, which can effectively address these limitations of natural botanicals. Based on our previous work, this project is intended to synthesize a Luteolin nanocomplex SPIO-DSPE-PEG-CRTIGPSVC/Luteolin (SDPC/Lut) with magnetic resonance imaging (MRI) traceability and BBB-targeted penetration. We attempt to explore the potential value of the novel nanomaterial SDPC/Lut in the treatment of AD by detecting the MRI traceability, BBB penetrability and regulation of BDNF/NF-κB inflammatory pathway from in vivo and in vitro studies.

阿尔茨海默病（AD）是常见的中枢神经系统退行性疾病，目前缺乏有效的治疗手段。有关天然植物药治疗AD的研究日益增多，我们既往发现木犀草素（Luteolin）可以有效减少LPS诱导的BV2细胞前炎症因子释放，并且能显著缓解AD小鼠脑内的炎症反应、提高脑源性神经营养因子（BDNF）水平以及改善AD小鼠的认知功能。然而，天然植物药生物利用度差，且穿透血脑屏障（BBB）的效率低下。我们既往成功合成了载药纳米粒子并验证了其入脑的高效性，可有效改善其不足之处。本项目拟基于前期工作，合成一种具有磁共振成像（MRI）可示踪性和BBB靶向穿透性强的Luteolin纳米复合物SPIO-DSPE-PEG-CRTIGPSVC/Luteolin（SDPC/Lut）。我们拟通过体内、体外研究，从MRI可示踪、BBB高效穿透以及调控BDNF/NF-κB炎症通路等多个角度探究新型纳米材料SDPC/Lut治疗AD的潜在价值。

阿尔茨海默病（AD）是常见的中枢神经系统退行性疾病，缺乏有效的治疗手段，天然植物药治疗AD极具潜力。本研究中，我们发现木犀草素（Luteolin）可以有效减少LPS诱导的BV2细胞前炎症因子释放，并且能显著缓解AD小鼠脑内的炎症反应、提高脑源性神经营养因子（BDNF）水平以及改善AD小鼠的认知功能；此外我们采用Neurotropin（NTP）通过增加神经元内源性BDNF表达，发现NTP可通过BDNF抑制Aβ的神经元毒性并进一步改善AD神经元病理沉积，以上研究为天然植物药治疗AD提供一定的理论依据。在本研究资助下，我们还探讨了无创神经调控技术三叉神经电刺激（TNS）治疗AD的作用，发现TNS可有效改善AD鼠的认知功能，其可能与增强神经元自噬、激活小胶质细胞吞噬功能、提高抗凋亡蛋白Bcl-2的表达等相关，为无创神经调控技术等新策略治疗AD提供新思路。