Research Laboratory of Cell Regulation, Shanghai Jiaotong University Medical School, 280 South Chongqing Road, Shanghai, China.
Neuroscience. 2009 Nov 10;163(4):1363-72. doi: 10.1016/j.neuroscience.2009.07.041. Epub 2009 Jul 24.
The purpose of this work is to study the effect of catalpol, an iridoid from Rehmannia glutinosa on neurodegenerative changes induced by beta-amyloid peptide Abeta(25-35) or Abeta(25-35)+ibotenic acid and the underlying mechanism. Results showed that catalpol significantly improved the memory deficits in the neurodegenerative mouse model produced by injection of Abeta(25-35)+ibotenic acid to the nucleus magnocellularis basalis, yet it is neither a cholinesterase inhibitor nor a muscarinic (M) receptor agonist. Instead, the choline acetyl transferase (ChAT) activity and the M receptor density in brain were significantly decreased in the model mice and catalpol could significantly elevate their levels. Furthermore, the brain-derived neurotrophic factor (BDNF) content in brain was significantly decreased in the model mice and catalpol elevated it to normal level (83%+/-3% and 102%+/-2% of normal respectively). There is a significant positive correlation between BDNF content and memory. Primary culture of forebrain neurons revealed that aggregated Abeta(25-35) induced significant decrease of ChAT positive neuron number, neurite outgrowth length, and M receptor density, while catalpol added to the culture medium 2 h prior to Abeta addition showed significant dose dependent protective effect. Notably, 24 h and 48 h after the addition of Abeta to the cultured cells, the BDNF mRNA level in the neurons decreased to 76%+/-7% and 66%+/-3% of control without catalpol treatment, but became 128%+/-17% and 131%+/-23% of control with catalpol treatment. When the action of BDNF was inhibited by k252a in the cultured neurons, the protective effect of catalpol was completely (neurite outgrowth length) or partially (ChAT positive neuron number and the M receptor density) abolished. Taken together, catalpol improves memory and protects the forebrain neurons from neurodegeneration through increasing BDNF expression. Whether catalpol could reverse the neurodegenerative changes already present before its application remains to be further studied.
本研究旨在探讨地黄苷元（Rehmannia glutinosa 的一种环烯醚萜）对β-淀粉样肽 Abeta（25-35）或 Abeta（25-35）+异恶唑乙酸诱导的神经退行性变化的影响及其作用机制。结果表明，地黄苷元可显著改善 Abeta（25-35）+异恶唑乙酸注射至基底神经节大细胞核引起的神经退行性病变模型小鼠的记忆缺陷，但它既不是乙酰胆碱酯酶抑制剂，也不是毒蕈碱（M）受体激动剂。相反，模型小鼠脑内的胆碱乙酰转移酶（ChAT）活性和 M 受体密度显著降低，而地黄苷元可显著提高其水平。此外，模型小鼠脑内脑源性神经营养因子（BDNF）含量显著降低，而地黄苷元可将其升高至正常水平（分别为正常水平的 83%+/-3%和 102%+/-2%）。BDNF 含量与记忆呈显著正相关。原代培养的大脑前神经元显示，聚集的 Abeta（25-35）诱导 ChAT 阳性神经元数量、神经突生长长度和 M 受体密度显著减少，而地黄苷元在 Abeta 添加至培养物前 2 小时添加至培养基中则表现出显著的剂量依赖性保护作用。值得注意的是，在添加 Abeta 至培养细胞 24 小时和 48 小时后，没有地黄苷元处理的神经元中的 BDNF mRNA 水平分别降至对照的 76%+/-7%和 66%+/-3%，但用地黄苷元处理的神经元中的 BDNF mRNA 水平分别升至对照的 128%+/-17%和 131%+/-23%。当在培养神经元中用 k252a 抑制 BDNF 的作用时，地黄苷元的保护作用完全（神经突生长长度）或部分（ChAT 阳性神经元数量和 M 受体密度）被消除。总之，地黄苷元通过增加 BDNF 表达来改善记忆并保护大脑前神经元免受神经退行性变。地黄苷元是否能逆转其应用前已经存在的神经退行性变化仍有待进一步研究。
