新型酪氨酸激酶抑制剂 AMN107（尼洛替尼）可使帕金森病小鼠纹状体运动行为正常化。

A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson's disease.

机构信息

Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima Tokushima, Japan ; Department of Neurobiology and Therapeutics, Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, University of Tokushima Tokushima, Japan.

Department of Neurobiology and Therapeutics, Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, University of Tokushima Tokushima, Japan.

出版信息

Front Cell Neurosci. 2014 Feb 20;8:50. doi: 10.3389/fncel.2014.00050. eCollection 2014.

Abnormal motor behaviors in Parkinson's disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylates cyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.

帕金森病（PD）中的异常运动行为是由于纹状体中多巴胺和谷氨酸传递之间的失衡导致的，这种失衡是由多巴胺和 cAMP 调节的 32kDa 磷酸蛋白（DARPP-32）整合的。c-Abelson 酪氨酸激酶（c-Abl）在 Tyr15 处磷酸化细胞周期蛋白依赖性激酶 5（Cdk5），以增加 Cdk5 的活性，通过在纹状体中磷酸化 DARPP-32 来减少多巴胺能信号的功效。在这里，我们报告在小鼠纹状体中，一种新型的 c-Abl 抑制剂 nilotinib（AMN107）抑制 Cdk5 在 Tyr15 处和 DARPP-32 在 Thr75 处的磷酸化，这是通过多巴胺受体激活通过 D2 受体介导的机制负调节的。像 D2-激动剂一样，nilotinib 与 D1-激动剂协同作用，诱导纹状体 c-Fos 表达。此外，系统给予 nilotinib 可使 1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的 PD 小鼠模型中的纹状体运动行为正常化。这些发现表明，nilotinib 可能可作为治疗 PD 运动症状的新的替代药物。