c-Abl Inhibition Exerts Symptomatic Antiparkinsonian Effects Through a Striatal Postsynaptic Mechanism.
c-Abl Inhibition Exerts Symptomatic Antiparkinsonian Effects Through a Striatal Postsynaptic Mechanism.
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DOI：
10.3389/fphar.2018.01311
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发表时间：
2018
影响因子：
5.6
通讯作者：
Goto S
中科院分区：
文献类型：
--
作者：
Zhou Y;Yamamura Y;Ogawa M;Tsuji R;Tsuchiya K;Kasahara J;Goto S
帕金森病(PD)是由黑质多巴胺能细胞进行性退化导致纹状体多巴胺缺乏所致。从抗帕金森病药物机制的角度来看，帕金森病的药物治疗可分为对症治疗和疾病修饰(神经保护)治疗。在PD条件下，Abelson非受体酪氨酸激酶(c-Abl)的水平和活性在人和小鼠的大脑中都被证实增加。在过去的十年中，人们观察到，抑制c-Abl活性有望防止帕金森病患者黑质多巴胺能细胞的退化，从而发挥抗帕金森病的作用。因此，c-Abl抑制剂已被临床应用为帕金森病治疗的一种疾病修正治疗策略。此外，在包括本文介绍的一系列研究中，实验证据表明，在N-甲基-4-苯基-1，2，3，6-四氢吡啶诱导的帕金森症小鼠模型中，c-Abl抑制通过正常化由CDK5(细胞周期蛋白依赖激酶5)和DARPP-32(多巴胺和环磷酸腺苷调节的磷蛋白32 kDa)介导的纹状体后突触后信号通路的活性变化，立即改善运动障碍。基于这一点，我们认为c-Abl抑制剂是一种理想的抗帕金森病药物，既有疾病修正作用，又有症状作用。未来的研究需要仔细评估与应用c-Abl抑制剂治疗帕金森病相关的疗效和临床挑战。
Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD.
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