title: A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson's disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Akie
authors.initials: A
authors.lastname: Tanabe
authors.affiliation: 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.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamamura
authors.affiliation: Department of Neurobiology and Therapeutics, Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, University of Tokushima Tokushima, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kasahara
authors.affiliation: Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima Tokushima, Japan.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Morigaki
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima Tokushima, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.affiliation: Department of Motor Neuroscience and Neurotherapeutics, Institute of Health Biosciences, Graduate School of Medical Sciences, University of Tokushima Tokushima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto
keywords: Cdk5; DARPP-32; Parkinson’s disease; c-Abl inhibitor; nilotinib