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Parkinson nilotinib

Richard K Wyse, Patrik Brundin, Todd B Sherer
We discuss a report in the current issue on clinical and biochemical findings from a safety trial using the cAbl tyrosine kinase inhibitor Nilotinib (150 mg or 300 mg given daily for 24 weeks) in a small group of patients with either advanced Parkinson's disease or Dementia with Lewy Bodies. Despite some side effects (one serious), the authors claim that Nilotinib, which is normally used at much higher doses for treating leukemia, is safe and tolerated. Furthermore, they report a possible benefit on motor and cognitive outcomes...
July 12, 2016: Journal of Parkinson's Disease
Fernando Pagan, Michaeline Hebron, Ellen H Valadez, Yasar Torres-Yaghi, Xu Huang, Reversa R Mills, Barbara M Wilmarth, Hellen Howard, Connell Dunn, Alexis Carlson, Abigail Lawler, Sean L Rogers, Ramsey A Falconer, Jaeil Ahn, Zhaoxia Li, Charbel Moussa
BACKGROUND: We evaluated the effects of low doses of the tyrosine kinase Abelson (Abl) inhibitor Nilotinib, on safety and pharmacokinetics in Parkinson's disease dementia or dementia with Lewy bodies. OBJECTIVES: The primary outcomes of this study were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory. METHODS: Twelve subjects were randomized into 150 mg (n = 5) or 300 mg (n = 7) groups and received Nilotinib orally every day for 24 weeks...
July 11, 2016: Journal of Parkinson's Disease
Senthilkumar S Karuppagounder, Saurav Brahmachari, Yunjong Lee, Valina L Dawson, Ted M Dawson, Han Seok Ko
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication...
2014: Scientific Reports
Akie Tanabe, Yukio Yamamura, Jiro Kasahara, Ryoma Morigaki, Ryuji Kaji, Satoshi Goto
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...
2014: Frontiers in Cellular Neuroscience
Anne-Laure Mahul-Mellier, Bruno Fauvet, Amanda Gysbers, Igor Dikiy, Abid Oueslati, Sandrine Georgeon, Allan J Lamontanara, Alejandro Bisquertt, David Eliezer, Eliezer Masliah, Glenda Halliday, Oliver Hantschel, Hilal A Lashuel
Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and α-synuclein (α-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates α-syn toxicity and clearance remain unknown...
June 1, 2014: Human Molecular Genetics
Michaeline L Hebron, Irina Lonskaya, Charbel E-H Moussa
The effects of ABL1/ABL inhibition on clearance of SNCA/α-synuclein were evaluated in animal models of α-synucleinopathies. Parkinson disease (PD) is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of SNCA. The tyrosine kinase ABL1 is activated in several neurodegenerative diseases. An increase in ABL1 activity is detected in human postmortem PD brains. Lentiviral expression of SNCA in the mouse SN activates ABL1 via phosphorylation, while lentiviral Abl expression increases SNCA levels...
August 2013: Autophagy
Michaeline L Hebron, Irina Lonskaya, Charbel E-H Moussa
Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of α-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of α-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases α-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of α-synuclein in transgenic and lentiviral gene transfer models...
August 15, 2013: Human Molecular Genetics
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