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Author Notes:

Corresponding Authors: Yan Yu Email: xuyanwxf@126.com Xuebing Cao Email: caoxuebing@126.com

GC collected the data, clustered the literature data, and wrote the paper.

SN collaborated in preparation of figures writing the paper. CH and KM collaborated in establishing the model.

YX and XC collaborated in writing the paper, supervised the overall work, and revised the paper.

ZZ collaborated in referencing the literature and revised the paper.

SP advised for data presentation and revised the paper.

Dr. Hanqi Yin (Shanghai Biotechnology Corporation) provided substantial help in microarray data analysis.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

This study was supported by the National Natural Science Foundation of China (NSFC Project No. 81171193, No.30700881, and No.81571249).

SP was supported by NIH grants NS045962, NS073994, NCRR RR000165, and ORIP/OD OD011132.

Keywords:

  • Parkinson's disease
  • L-DOPA-induced dyskinesia
  • p-ERK1/2
  • ΔFosB
  • TH
  • ARNT
  • PD98059
  • microarray

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

Journal Title:

Frontiers in Neuroscience

Volume:

Volume 11

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L-DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including ΔFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, ΔFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy.

Copyright information:

© 2017 Chen, Nie, Han, Ma, Xu, Zhang, Papa and Cao.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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