Sinha Anshuman, Tamboli Riyaj S, Seth Brashket, Kanhed Ashish M, Tiwari Shashi Kant, Agarwal Swati, Nair Saumya, Giridhar Rajani, Chaturvedi Rajnish Kumar, Yadav Mange Ram
Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The MS University of Baroda, Vadodara, 390001, Gujarat, India.
Mol Neurobiol. 2015 Aug;52(1):638-52. doi: 10.1007/s12035-014-8899-y. Epub 2014 Sep 26.
It has been reported in the literature that cholinesterase inhibitors provide protection in Alzheimer's disease (AD). Recent reports have implicated triazine derivatives as cholinesterase inhibitors. These findings led us to investigate anti-cholinestrase property of some novel triazine derivatives synthesized in this laboratory. In vitro cholinesterase inhibition assay was performed using Ellman method. The potent compounds screened out from in vitro assay were further evaluated using scopolamine-induced amnesic mice model. Further, in vitro reactive oxygen species (ROS) scavenging and anti-apoptotic property of the potent compounds were demonstrated against Aβ1-42-induced neurotoxicity in rat hippocampal cells. Their neuroprotective role was assessed using Aβ1-42-induced Alzheimer's-like phenotype in rats. Further, the role of compounds on the activation of the Wnt/β-catenin pathway was studied. The results showed that the chosen compounds are having protective effect in Alzheimer's-like condition; the ex vivo results advocated their anti-cholinestrase and anti-oxidant activities. Treatment with TRZ-15 and TRZ-20 showed neuroprotective ability of the compounds as evidenced from the improved cognitive ability in the animals, and decrease in Aβ1-42 burden and cytochrome c and cleaved caspase-3 levels in the brain. This study also demonstrates positive involvement of the novel triazine derivatives in the Wnt/β-catenin pathway. Immunoblot and immunofluorescence data suggested that ratio of pGSK3/GSK3 and β-catenin got dramatically improved after treatment with TRZ-15 and TRZ-20. TRZ-15 and TRZ-20 showed neuroprotection in scopolamine-induced amnesic mice and Aβ1-42-induced Alzheimer's rat model and also activate the Wnt/β-catenin signaling pathway. These findings conclude that TRZ-15 and TRZ-20 could be a therapeutic approach to treat AD.
文献报道胆碱酯酶抑制剂对阿尔茨海默病（AD）具有保护作用。近期报道表明三嗪衍生物具有胆碱酯酶抑制作用。这些发现促使我们研究本实验室合成的一些新型三嗪衍生物的抗胆碱酯酶特性。采用埃尔曼法进行体外胆碱酯酶抑制试验。从体外试验中筛选出的强效化合物，进一步利用东莨菪碱诱导的记忆缺失小鼠模型进行评估。此外，还针对Aβ1-42诱导的大鼠海马细胞神经毒性，证明了强效化合物的体外活性氧（ROS）清除和抗凋亡特性。利用Aβ1-42诱导的大鼠阿尔茨海默病样表型评估它们的神经保护作用。此外，还研究了化合物对Wnt/β-连环蛋白信号通路激活的作用。结果表明，所选化合物在阿尔茨海默病样病症中具有保护作用；体外实验结果证实了它们的抗胆碱酯酶和抗氧化活性。TRZ-15和TRZ-20处理显示出这些化合物的神经保护能力，动物认知能力的改善、脑中Aβ1-42负荷以及细胞色素c和裂解的半胱天冬酶-3水平的降低都证明了这一点。本研究还证明了新型三嗪衍生物在Wnt/β-连环蛋白信号通路中的积极作用。免疫印迹和免疫荧光数据表明，TRZ-15和TRZ-20处理后，pGSK3/GSK3与β-连环蛋白的比例显著提高。TRZ-15和TRZ-20在东莨菪碱诱导的记忆缺失小鼠和Aβ1-42诱导的阿尔茨海默病大鼠模型中显示出神经保护作用，并且还激活了Wnt/β-连环蛋白信号通路。这些发现得出结论，TRZ-15和TRZ-20可能是治疗AD的一种治疗方法。
