Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl-(1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N-propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagiline. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases.

译文

我们的研究为抗帕金森药物雷沙吉兰 [N-炔丙基-(1R)-氨基吲哚] 的神经保护生物学机制提供了新的见解,涉及Bcl-2家族蛋白与蛋白激酶C (PKC) 途径的关联。在血清戒断诱导的大鼠嗜铬细胞瘤PC12细胞凋亡模型中,雷沙吉兰及其炔丙基部分N-炔丙胺通过多种神经保护途径减少细胞死亡,包括刺激PKC磷酸化; PKCepsilon mRNA的上调; Bcl-X(L),Bcl-w,和脑源性神经营养因子 (BDNF) mrna; 以及PKCgamma,Bad和Bax mrna的下调。此外,这些药物抑制了pro-caspase-3和聚 (ADP-核糖) 聚合酶 (PARP) 的裂解和激活,而PKC抑制剂GF109203X逆转了这些作用。此外,雷沙吉兰降低了无血清诱导的细胞死亡的重要调节剂Bad的水平,这也被GF109203X阻断,表明雷沙吉兰参与了PKC依赖性细胞存活活性。结构活性研究已经确定,N-炔丙胺对于雷沙吉兰的新型神经保护和神经元细胞存活活性至关重要,因为该部分本身揭示了类似的保护作用和作用机制。这些结果使我们开发了几种含有炔丙基部分和铁螯合性质的多功能神经保护药物,用于治疗和/或预防神经退行性疾病。

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