c-Abl抑制剂应用于治疗帕金森病的进展研究

Application of c-Abl inhibitors in the treatment of Parkinson's disease

帕金森病(PD)是与衰老相关的常见的神经退行性疾病。近年来,有关PD的动物模型研究和对来自PD患者的脑标本的分析发现多巴胺能神经元中非受体酪氨酸激酶Abelson(c-Abl)的水平和活性增加。c-Abl具有蛋白质底物磷酸化活性,可使α-突触核蛋白和E3泛素连接酶Parkin磷酸化。临床上用于治疗白血病的c-Abl激酶抑制剂,在PD的细胞和动物模型均中显示出神经保护作用,这为临床上使用c-Abl抑制剂治疗PD患者提供了良好的应用前景。文章就c-Abl及其与PD发生发展的病理生理过程的关系进行综述,并对目前c-Abl抑制剂的药理学和安全性相关的问题进行了讨论。c-Abl抑制剂是否能够真正用于临床治疗PD使更多患者受益,仍需要更严格控制、设计良好的试验做进一步的研究。

Parkinson＇s disease （PD） is a common neurodegenerative disorder associated with aging. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson （c-Abl） in dopaminergic neurons with phosphorylation of protein substrates, such as a-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leu- kemia has shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optim- ism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c- Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.