title: Inhibition of Glycogen Synthase Kinase-3β (GSK-3β) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats.
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, respectively), 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.
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Cheng-long
authors.initials: CL
authors.lastname: Xie
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Su-fang
authors.initials: SF
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Xi-Jin
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Zhen-Guo
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000008:administration & dosage; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000150:complications*; D010766:Phosphorylation; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists; D013830:Thiadiazoles / Q000008:administration & dosage*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D017447:Receptors, Dopamine D1; D013830:Thiadiazoles; D016875:tau Proteins; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3