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Front. Pharmacol. | doi: 10.3389/fphar.2018.01311

c-Abl inhibition exerts symptomatic antiparkinsonian effects through a striatal postsynaptic mechanism

 YU ZHOU1, Yukio Yamamura1, Masatoshi Ogawa1, Ryosuke Tsuji1, Koichiro Tsuchiya1,  Jiro Kasahara1 and  Satoshi Goto1*
  • 1Tokushima University, Japan

Parkinson's disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD.

Keywords: c-Abl, Parkinson ' s disease, CDK5, Striatum, DARPP-32

Received: 21 Aug 2018; Accepted: 29 Oct 2018.

Edited by:

Mahmoud Iravani, University of Hertfordshire, United Kingdom

Reviewed by:

Ciaran J. Faherty, Alkermes (United States), United States
Anjali M. Rajadhyaksha, Weill Cornell Medicine, Cornell University, United States  

Copyright: © 2018 ZHOU, Yamamura, Ogawa, Tsuji, Tsuchiya, Kasahara and Goto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) 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.

* Correspondence: Prof. Satoshi Goto, Tokushima University, Tokushima, 770-8501, Tokushima, Japan, sgoto@clin.med.tokushima-u.ac.jp