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.
Highlights
L-DOPA-induced dyskinesia (LID) that are associated with chronic dopamine replacement therapy still represent one of the major problems in the management of patients with Parkinson’s disease
Chronic L-DOPA administration (12 mg/kg, s.c., once daily for 21 days, Figure 2A) to rats with unilateral nigrostriatal 6-OHDA lesion led to the development of increasingly severe abnormal involuntary movements (AIMs) and rotation, all reaching a plateau after day 9 (Figure 2B, LID and LID + Vehicle groups)
L-DOPA administration induced a significant increase in p-ERK1/2 level in the striatum of unilaterally 6-OHDAlesioned rats (Figures 3A,B, Supplementary Figure 1). This effect was prevented by the inhibitor of mitogen-activated protein kinase kinase (MEK) PD98059 [Figures 3A,B, Supplementary Figure 1; p-ERK1/2 vs. ERK1/2, F(4, 15) = 6.244 one-way analysis of variance (ANOVA) followed by Tukey HSD and LSD post-hoc test, N = 4/group]
Summary
L-DOPA-induced dyskinesia (LID) that are associated with chronic dopamine replacement therapy still represent one of the major problems in the management of patients with Parkinson’s disease. The dopamine D1 receptor signaling pathway is associated with overactivation of ERK1/2 in rodent models of LID (Westin et al, 2007; Darmopil et al, 2009; Feyder et al, 2011). ERK1/2 was found to be the downstream signaling of the cAMP/PKA/DARPP-32 pathway in animal models of LID, studies have been inconsistent (Santini et al, 2007; Dupre, 2008; Gerfen et al, 2008; Lebel et al, 2010). ERK1/2 appears to activate the mammalian target of rapamycin complex 1 (mTORC1) (Roux et al, 2007; Carriere et al, 2008) that is a critical regulator of mRNA translation especially in relation to long-lasting synaptic plasticity and memory (CostaMattioli et al, 2009). Rapamycin and CCI-779, the inhibitor of mTOR, modify mTORC1 targets and can reduce abnormal involuntary movements (AIMs) in rodents (Santini et al, 2009b; Decressac and Björklund, 2013)
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