Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
Department of Pharmaceutics, School of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, China.
Phytomedicine. 2024 Jul 25;130:155753. doi: 10.1016/j.phymed.2024.155753. Epub 2024 May 16.
Meningeal lymphatic vessels (mLVs) have great potential to be the therapeutic target for β Amyloid protein (Aβ) clearing in Alzheimer's disease (AD), but the regulatory methods of the mLVs are limited. The lymphatic valve, marked by FOXC2, is the fundamental structure for maintaining stable lymphatic drainage function. Preliminary evidence suggested that borneol (BO) as the classical phytochemicals could enhance the expression of FOXC2 in the mLVs of healthy mice.
This study aims to explore the regulatory ability of BO on lymphatic valves of mLVs in the AD model mice.
We used the intracerebroventricular injection of Aβ42 oligomers to construct the AD-like symptoms model induced by toxic protein deposition. We administered BO nano micelles(BO-Ms) orally before and after to simulate the AD prevention and treatment strategy.
Herein, this study characterized the efficacy and pathways of BO-Ms for regulating mLVs in AD model by Rt-PCR, WB and confocal microscopy, and determined the effects of BO-Ms on Aβ clearance, behavior and safety of AD mice.
The AD modeling process severely impaired the expression of lymphatic valves. However, after oral administering BO-Ms for prevention and treatment, an increase in the lymphatic valves of the transverse sinus was observed, which derived from the up-regulation of the transcription factor (FOXC2 and Akt) and the down-regulation of the transcription inhibitors (FOXO1 and PRDM1). Furthermore, the effects of BO-Ms on the lymphatic valves could enhance the lymphatic drainage of the mLVs in AD-like mice, promoting the clearance of toxicity aggregates, protecting neurons, and alleviating AD-like symptoms. Simultaneously, continuous oral BO-Ms for 30 days didn't show any significant organ toxicity. The most important thing was that the preventive effect of BO administration was superior to therapeutic administration in all data.
In summary, our research indicated that BO is a promoter of lymphatic valve formation in the mLVs, and could prevent or repair damage caused by toxic Aβ42. BO was the only bioactive natural product with the ability to regulate mLVs valves. Thus, BO has the potential to become phytochemicals for alleviating AD symptoms by enhancing the drainage function of mLVs.
脑膜淋巴管（mLVs）在清除阿尔茨海默病（AD）β淀粉样蛋白（Aβ）方面具有很大的治疗潜力，但 mLVs 的调节方法有限。淋巴管瓣膜由 FOXC2 标记，是维持稳定的淋巴引流功能的基本结构。初步证据表明，作为经典植物化学物质的冰片（BO）可以增强健康小鼠 mLVs 中 FOXC2 的表达。
本研究旨在探讨 BO 对 AD 模型小鼠 mLVs 淋巴管瓣膜的调节能力。
我们使用脑室内注射 Aβ42 寡聚体构建由毒性蛋白沉积引起的 AD 样症状模型。我们在前后口服 BO 纳米胶束（BO-Ms）模拟 AD 预防和治疗策略。
本研究通过 Rt-PCR、WB 和共聚焦显微镜来表征 BO-Ms 调节 AD 模型中 mLVs 的功效和途径，并确定 BO-Ms 对 AD 小鼠 Aβ 清除、行为和安全性的影响。
AD 建模过程严重损害了淋巴管瓣膜的表达。然而，口服 BO-Ms 进行预防和治疗后，观察到横窦淋巴管瓣膜增加，这源自转录因子（FOXC2 和 Akt）的上调和转录抑制剂（FOXO1 和 PRDM1）的下调。此外，BO-Ms 对淋巴管瓣膜的作用可以增强 AD 样小鼠 mLVs 的淋巴引流，促进毒性聚集物的清除，保护神经元，并缓解 AD 样症状。同时，连续口服 BO-Ms 30 天不会引起任何明显的器官毒性。最重要的是，BO 给药的预防效果优于治疗效果。
总之，我们的研究表明，BO 是 mLVs 淋巴管瓣膜形成的促进剂，可以预防或修复毒性 Aβ42 引起的损伤。BO 是唯一具有调节 mLVs 瓣膜能力的生物活性天然产物。因此，BO 有可能通过增强 mLVs 的引流功能成为缓解 AD 症状的植物化学物质。
