Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Neurodegener Dis. 2010;7(4):219-31. doi: 10.1159/000265946. Epub 2010 Feb 27.
The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD).
Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism.
METHODS/RESULTS: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail.
These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.
抗帕金森单胺氧化酶 B 抑制剂雷沙吉兰似乎是治疗早期帕金森病 (PD) 的第一种神经保护疾病修饰疗法。
我们采用多药治疗范式，测试雷沙吉兰独特的神经保护药理学特征是否可以与绿茶中主要的抗氧化剂/铁螯合剂多酚儿茶素 -3-没食子酸酯（EGCG）互补，并恢复动物帕金森病中受损的神经元丢失和分子靶点。
方法/结果：我们通过高效液相色谱、免疫组织化学和 Western blot 分析表明，雷沙吉兰和 EGCG 的组合以亚有效剂量（对神经没有显著保护作用）发挥协同作用，可恢复 MPTP 处理的小鼠黑质纹状体通路。详细分析显示这些药物具有互补作用，可在黑质中对 MPTP 损伤的分子/靶点（SN）产生不同的作用：雷沙吉兰诱导脑源性神经营养因子的产生，EGCG 增加蛋白激酶 C α 同工型的膜水平，以及它们下游效应物丝氨酸/苏氨酸激酶 Akt/蛋白激酶 B 的协同补充，表明该激酶可能是药物鸡尾酒不同作用机制的一个交汇点。
这些结果为分子证据提供了依据，即雷沙吉兰和 EGCG 的组合激活多个脑靶标可能协同促进 SN 中多巴胺神经元的挽救和纹状体多巴胺的补充。这对于接受雷沙吉兰治疗的 PD 患者可能具有重要意义，他们可能会从 EGCG 的辅助治疗中进一步受益。
