MRI引导低频聚焦超声联合纳米微泡转染Nrf2治疗帕金森病的研究

Parkinson's disease (PD) is a very common disorder which lacks efficient therapy and deserves attention. Blood-brain-barrier (BBB) protects the brain and in the meanwhile makes about 90% drugs and nucleotides unable to be delivered into the brain thus prohibits the development of gene therapy for PD. The MRI-guided focused ultrasound microbubble is competent for opening BBB and improves transfection efficiency, so it has been applied in some research of intracranial tumors, however it has not been reported in PD. Mechanisms for PD is still not well understood, among which reactive oxidative stress (ROS) plays an important role. Nrf2 is a nuclear factor which activates the antioxidant response element (ARE) pathway and is supposed to protect PD by the way of regulating redox status. The present study aims to deliver Nrf2 contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, so as to explore the effect of opening BBB of the method, and to confirm the treatment of Nrf2 overexpression in PD.

帕金森病（PD）以其高发性和缺少有效的治疗方法而备受关注，而血脑屏障（BBB）在维护脑稳态的同时也成为大部分治疗药物及基因入脑的难以逾越的屏障，更是PD基因治疗的瓶颈。MRI引导下低频聚焦超声联合微泡可克服BBB实现静注药物或核酸类靶向治疗颅内疾病，但据我们所知，该项新技术尚未在PD中得到应用。另外活性氧簇（ROS）是黑质多巴胺能神经元选择性损伤的关键因素，也是PD的重要发病机制之一，而核转录因子Nrf2可激活抗氧化反应元件（ARE），参与PD的保护机制，因此是PD基因治疗的理想靶点。为克服BBB的限制，该研究将首次探讨MRI引导下的低频聚焦超声联合纳米微泡开放PD大鼠黑质BBB并转染Nrf2基因实现对PD的治疗作用，以寻找能突破BBB的高效、安全的新方法。

帕金森病（PD）以其高发性和缺少有效的治疗方法而备受关注，而血脑屏障（BBB）在维护脑稳态的同时也成为大部分治疗药物及基因入脑的难以逾越的屏障，更是PD基因治疗的瓶颈。MRI引导下低频聚焦超声联合微泡可克服BBB实现静注药物或核酸类靶向治疗颅内疾病。另外活性氧簇（ROS）是黑质多巴胺能神经元选择性损伤的关键因素，也是PD的重要发病机制之一，而核转录因子Nrf2可激活抗氧化反应元件（ARE），参与PD的保护机制，因此是PD基因治疗的理想靶点。据我们所知，目前只有一个利用低频聚焦超声联合微泡转染BDNF治疗PD的动物实验。为克服BBB的限制，该研究将首次探讨MRI引导下的低频聚焦超声联合纳米微泡开放PD大鼠黑质BBB并转染Nrf2基因实现对PD的治疗作用，以寻找能突破BBB的高效、安全的新方法。该实验中我们使用薄膜水化-声振法制备成功制备了直径约400nm的纳米微泡，使用MRI引导低频聚焦超声联合纳米微泡促进Nrf2质粒靶向转染到PD模型大鼠的黑质，显著提高转染效率，通过定量PCR和western blot证实低频聚焦超声联合纳米微泡促进了Nrf2的RNA和蛋白表达，并减少了ROS的含量，TH和DAT免疫组化证实其减少了氧化应激对多巴胺能神经元的损伤。我们的实验是首次利用低频聚焦超声联合纳米微泡进行颅内靶向转染通过抑制氧化应激起到保护黑质神经元的作用。