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ID 114464
Title Alternative
Nilotinib exerts antiparkinsonian actions
Author
Tanabe, Akie University of Tokushima
Yamamura, Yukio University of Tokushima
Keywords
nilotinib
c-Abl inhibitor
Cdk5
DARPP-32
Parkinson’s disease
Content Type
Journal Article
Description
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.
Journal Title
Frontiers in Cellular Neuroscience
ISSN
16625102
Publisher
Frontiers Media S.A.
Volume
8
Start Page
50
Published Date
2014-02-20
Rights
© 2014 Tanabe, Yamamura, Kasahara, Morigaki, Kaji and Goto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)( https://creativecommons.org/licenses/by/3.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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language
eng
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departments
Pharmaceutical Sciences
Medical Sciences