Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients
Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin
In this regard more carefully designed and well-controlled trials with PD patients are required to arrive at a conclusion regarding the potential benefits of c-Abl inhibitors in the treatment of PD
Summary
Nilotinib (AMN107, Tasigna) is a second-generation c-Abl tyrosine kinase inhibitor that is used in CML in a daily dose of 300 mg to over 1000 mg per patient (Weisberg et al, 2006). The drug is relatively safe and tolerated but in some patients heart complications have been associated with the use of nilotinib, and a black box warning has been given to the drug by the USA Food and Drug Administration. Preclinical studies show that nilotinib penetrates into brain tissue and was neuroprotective in two TABLE 1 | Some properties of current c-Abl inhibitors
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