Graduate Program of Biomolecular Sciences, Institute of Natural and Applied Sciences , Canakkale Onsekiz Mart University , Canakkale , 17020 Turkey.
Graduate Program of Molecular Biology and Genetics, Institute of Natural and Applied Sciences , Canakkale Onsekiz Mart University , Canakkale , 17020 Turkey.
ACS Chem Neurosci. 2020 Feb 19;11(4):501-507. doi: 10.1021/acschemneuro.9b00694. Epub 2020 Feb 6.
Neuropathological changes in Alzheimer's disease (AD) are directly linked to the early inflammatory microenvironment in the brain. Therefore, disease-modifying agents targeting neuroinflammation may open up new avenues in the treatment of AD. Strigolactones (SLs), subclasses of structurally diverse and biologically active apocarotenoids, have been recently identified as novel phytohormones. In spite of the remarkable anticancer capacity shown by SLs, their effects on the brain remained unexplored. Herein, the SIM-A9 microglial cell line was used as a phenotypic screening tool to search for the representative SL, GR24, demonstrating marked potency in the suppression of lipopolysaccharide (LPS)-induced neuroinflammatory/neurotoxic mediators by regulating NF-κB, Nrf2, and PPARγ signaling. GR24 also in the brain endothelial cell line bEnd.3 mitigated the LPS-increased permeability as evidenced by reduced Evans' blue extravasation through enhancing the expression of tight junction protein, occludin. Collectively, the present work shows the anti-neuroinflammatory and glia/neuroprotective properties of GR24, making SLs promising scaffolds for the development of novel anti-AD candidates.
阿尔茨海默病（AD）的神经病理学变化与大脑中早期炎症的微环境直接相关。因此，针对神经炎症的疾病修饰药物可能为 AD 的治疗开辟新途径。独脚金内酯（SLs）是结构多样且具有生物活性的类胡萝卜素的亚类，最近被确定为新型植物激素。尽管 SLs 表现出显著的抗癌能力，但它们对大脑的影响仍未得到探索。在此，我们使用 SIM-A9 小胶质细胞系作为表型筛选工具来寻找代表性的 SL，GR24，通过调节 NF-κB、Nrf2 和 PPARγ 信号通路，显示出在抑制脂多糖（LPS）诱导的神经炎症/神经毒性介质方面的显著功效。GR24 还可以减轻脑内皮细胞系 bEnd.3 中的 LPS 增加的通透性，这表现为通过增强紧密连接蛋白闭合蛋白的表达减少 Evans 蓝外渗。总的来说，本研究表明 GR24 具有抗神经炎症和神经胶质/神经保护作用，使 SL 成为开发新型抗 AD 候选药物的有前途的支架。
