Research Laboratory of Cell Regulation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Neurochem. 2012 Mar;120(6):1072-83. doi: 10.1111/j.1471-4159.2011.07635.x. Epub 2012 Feb 6.
Parkinson's disease is a chronic neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. New therapeutic approaches aiming at delaying or reversing the neurodegenerative process are under active investigations. In this work, we found that harpagoside, an iridoid purified from the Chinese medicinal herb Scrophularia ningpoensis, could not only prevent but also rescue the dopaminergic neurodegeneration in MPTP/MPP(+) intoxication with promising efficacy. Firstly, in cultured mesencephalic neurons, harpagoside significantly attenuated the loss of TH-positive neuron numbers and the shortening of axonal length. Secondly, in a chronic MPTP mouse model, harpagoside dose-dependently improved the loco-motor ability (rotarod test), increased the TH-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) and increased the striatal DAT density ((125) I-FP-CIT autoradiography). Thirdly, harpagoside markedly elevated the GDNF mRNA and GDNF protein levels in MPTP/MPP(+) lesioned models. However, the protecting effect of harpagoside on the dopaminergic degeneration disappeared when the intrinsic GDNF action was blocked by either the Ret inhibitor PP1 or the neutralizing anti-GDNF antibody. Taken together, we conclude that harpagoside attenuates the dopaminergic neurodegeneration and movement disorder mainly through elevating glial cell line-derived neurotrophic factor.
帕金森病是一种慢性神经退行性运动障碍，其特征是黑质致密部多巴胺能神经元丧失。目前正在积极研究旨在延缓或逆转神经退行性过程的新治疗方法。在这项工作中，我们发现哈巴俄苷，一种从中国草药胡芦巴中分离出来的环烯醚萜，不仅可以预防，而且可以挽救 MPTP/MPP(+)中毒引起的多巴胺能神经退行性变，具有良好的疗效。首先，在培养的中脑神经元中，哈巴俄苷显著减轻了 TH 阳性神经元数量的减少和轴突长度的缩短。其次，在慢性 MPTP 小鼠模型中，哈巴俄苷剂量依赖性地改善了运动能力（转棒试验），增加了黑质致密部的 TH 阳性神经元数量（无偏立体学计数），并增加了纹状体 DAT 密度（(125)I-FP-CIT 放射自显影）。第三，哈巴俄苷显著提高了 MPTP/MPP(+)损伤模型中的 GDNF mRNA 和 GDNF 蛋白水平。然而，当内在的 GDNF 作用被 Ret 抑制剂 PP1 或中和抗 GDNF 抗体阻断时，哈巴俄苷对多巴胺能变性的保护作用消失了。综上所述，我们得出结论，哈巴俄苷通过提高胶质细胞源性神经营养因子来减轻多巴胺能神经退行性变和运动障碍。
