Research Laboratory of Cell Regulation, Shanghai Jiaotong University Medical School, 280 South Chongqing Road, Shanghai 200025, China.
Brain Res. 2012 Mar 2;1441:27-37. doi: 10.1016/j.brainres.2012.01.008. Epub 2012 Jan 17.
Our previous studies demonstrate that a non-cholinesterase inhibitor (AChEI) compound catalpol, purified from a traditional Chinese medicinal herb Rehmannia glutinosa, could improve the symptoms and pathological changes in animal and cellular models of memory related neurodegenerative diseases. In this study, we compared catalpol with the most commonly used AChEI donepezil in respect to their mechanism of action on the neurodegenerative changes in an animal model induced by beta-amyloid (Aβ) plus glutamate receptor agonist. It was found that the model mice showed significant deficit in the learning ability and memory in Y maze avoidance test, and meanwhile both donepezil and catalpol greatly improve the learning ability and memory after 2 to 3 months' administration. At the selected doses, donepezil only partially raised the declined brain muscarinic acetylcholine receptor (M receptor) density and choline acetyltransferase (ChAT) activity resulting in these levels still lower than normal control, while catalpol completely retrieved these two parameters. ELISA revealed that catalpol, instead of donepezil, possessed the capability of elevating the declined brain BDNF level of the animal model. The ELISA results on the BDNF protein level was confirmed by quantitative RT-PCR measurement of BDNF mRNA in Aβ₂₅₋₃₅-treated primary culture of forebrain neurons. In combination with our previous work, we think the neuroprotective effects of donepezil and catalpol are mediated through different mechanisms. Since BDNF has been proved to be an important intrinsic factor in protecting neurodegenerative diseases, catalpol may be a hopefully effective compound against neurodegenerative changes induced by Aβ and glutamate receptor agonist.
我们之前的研究表明，一种非胆碱酯酶抑制剂（AChEI）化合物梓醇，从传统中药地黄中纯化而来，可以改善与记忆相关的神经退行性疾病的动物和细胞模型中的症状和病理变化。在这项研究中，我们比较了梓醇和最常用的 AChEI 多奈哌齐在β-淀粉样蛋白（Aβ）加谷氨酸受体激动剂诱导的动物模型中对神经退行性变化的作用机制。结果发现，模型小鼠在 Y 迷宫回避试验中表现出明显的学习能力和记忆缺陷，同时多奈哌齐和梓醇在 2 至 3 个月的给药后都大大改善了学习能力和记忆。在选定的剂量下，多奈哌齐仅部分提高了下降的脑毒蕈碱乙酰胆碱受体（M 受体）密度和胆碱乙酰转移酶（ChAT）活性，导致这些水平仍低于正常对照，而梓醇则完全恢复了这两个参数。ELISA 显示，梓醇而非多奈哌齐具有提高动物模型下降的脑 BDNF 水平的能力。β淀粉样蛋白（Aβ）25-35 处理的大脑前神经元原代培养物中 BDNF mRNA 的定量 RT-PCR 测量证实了 ELISA 对 BDNF 蛋白水平的结果。结合我们之前的工作，我们认为多奈哌齐和梓醇的神经保护作用是通过不同的机制介导的。由于 BDNF 已被证明是保护神经退行性疾病的重要内在因素，梓醇可能是一种有希望的有效化合物，可对抗 Aβ和谷氨酸受体激动剂诱导的神经退行性变化。
