title: Single or combined treatment with L-DOPA and quinpirole differentially modulate expression and phosphorylation of key regulatory kinases in neuroblastoma cells.
abstract: In the past decades, the clinical use of dopamine agonists has expanded from adjunct therapy in patients with a deteriorating response to L-3,4-dihydroxyphenylalanine (L-DOPA) to monotherapy for the treatment of early PD. Dopamine agonists provide their antiparkinsonian benefit through stimulation of brain postsynaptic type 2 dopamine receptors that exert their effect through classical cAMP-dependent mechanisms, as well as cAMP-independent cellular signaling cascades, including the Akt/glycogen synthase kinase 3 (GSK3) pathway. Alterations of Akt/GSK3 have been observed and may contribute to the neurodegenerative processes and the development of L-DOPA-induced dyskinesia. The effects L-DOPA and quinpirole, a dopamine agonist, on the two key regulatory kinases, Akt and GSK3, were evaluated in neuroblastoma cell line. L-DOPA and dopamine agonist dose-dependently and differentially modulated Akt and GSK3 expression and phosphorylation when added alone or combined. The combined treatment inverted or potentiated the modulatory properties of the single compound. The drug- and concentration-dependent balance of dopamine receptor stimulation over auto-oxidation may distinctively modulate GSK3 isoforms and Akt. Our results indicate that particular attention must be given to drug concentration and combination when multiple therapies are applied for the clinical treatment of PD patients.
authors.affiliation: Laboratory of Functional Neurochemistry, C. Mondino National Neurological Institute, via Mondino 2, Pavia, Italy. Electronic address: marie.armentero@mondino.it.
authors.forename: Marie Therese
authors.initials: MT
authors.lastname: Fuzzati-Armentero
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghezzi
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Adriano
authors.initials: A
authors.lastname: Oda
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology*
chemical_list: D018491:Dopamine Agonists; D019257:Quinpirole; D007980:Levodopa; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Akt; DA; DR; Dopamine agonists; GSK3; L-3,4-dihydroxyphenylalanine; MTT; Neurodegeneration; PD; Parkinson's disease; SH-SY5Y cells; SNc; dopamine; dopamine receptor; glycogen synthase kinase 3; l-DOPA; substantia nigra pars compacta