Inhibition of Glycogen Synthase Kinase-3β (GSK-3β) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats.

Cheng-Long Xie,Yu Zhang,Xi-Jin Wang,Mei-Hua Wang,Su-Fang Zhang,Jing-Ya Lin,Zhen-Guo Liu

doi:10.1038/srep23527

Cheng-Long Xie, Yu Zhang + Show 5 more

Open Access

https://doi.org/10.1038/srep23527

Copy DOI

Journal: Scientific reports	Publication Date: Mar 21, 2016
Citations: 27	License type: CC BY 4.0

Affiliation: XinHua Hospital

Abstract

Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson’s disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3β (GSK-3β) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, reapectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3β played an important role in the development and expression of LID. Inhibition of GSK-3β with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats.

Highlights

A number of studies suggested that treatment with L-dopa at high concentrations increased Glycogen Synthase Kinase-3 (GSK-3) activity and resulted in neuronal injury[6]
Previous study reported that bilateral models of Parkinson’s disease (PD) as MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkeys, increased activation of Glycogen Synthase Kinase-3β (GSK-3β) was associated with L-dopa-induced dyskinesias[7]
Those treated with L-dopa plus benserazide (LID group, n = 4) were showed high levels of GSK-3β and low level of phoso-GSK-3β when compared with 6-OHDA lesioned rats (PD group, n = 4) and normal control rats (Sham groups, n = 4) in the striatum lysis (P < 0.05 compared with PD groups and Sham groups, Fig. 2A,B)

Summary

Introduction

A number of studies suggested that treatment with L-dopa at high concentrations increased Glycogen Synthase Kinase-3 (GSK-3) activity and resulted in neuronal injury[6]. Previous study reported that bilateral models of PD as MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkeys, increased activation of GSK-3β was associated with L-dopa-induced dyskinesias[7]. In animal models of L-dopa-induced dyskinesia, there is still limited data on GSK-3β expression involve in development of LID. In the present study was mainly to investigate whether GSK-3β inhibitor against AIM score in a rat model of LID. We used selective GSK-3β inhibitor TDZD8 (4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) to explore the involvement of GSK-3β in protein tau phosphorylation. We investigated the molecular mechanisms associated with the antidyskinetic effects of TDZD8 (1 mg/kg and 2 mg/kg) and assessed the occurrence of AIM score and the performance of motor function, as well as PKA activity and/or DARPP-32, ERK phosphorylation in the striatum of LID rats

Methods

Results

Conclusion