title: Rotigotine protects against glutamate toxicity in primary dopaminergic cell culture.
abstract: In Parkinson disease the degeneration of dopaminergic neurones is believed to lead to a disinhibition of the subthalamic nucleus thus increasing the firing rate of the glutamatergic excitatory projections to the substantia nigra. In consequence, excessive glutamatergic activity will cause excitotoxicity and oxidative stress. In the present study we investigated mechanisms of glutamate toxicity and the neuroprotective potential of the dopamine agonist rotigotine towards dopaminergic neurones in mouse mesencephalic primary culture. Glutamate toxicity was mediated by the N-methyl-d-aspartic acid (NMDA) receptor and accompanied by a strong calcium influx into dopaminergic neurones for which the L-type voltage-sensitive calcium channels play an important role. The rate of superoxide production in the culture was highly increased. Deleterious nitric oxide production did not participate in glutamate-mediated excitotoxicity. Pretreatment of cultures with rotigotine significantly increased the survival of dopaminergic neurones exposed to glutamate. Rotigotine exerted its protective effects via dopamine receptor stimulation (presumably via dopamine D3 receptor) and decreased significantly the production of superoxide radicals. When cultures were preincubated with Phosphoinositol 3-Kinase (PI3K) inhibitors the protective effect of rotigotine was abolished suggesting a decisive role of the PI3K/Akt pathway in rotigotine-mediated neuroprotection. Consistently, exposure to rotigotine induced the activation of Akt by phosphorylation followed by phosphorylation, and thus inactivation, of the pro-apoptotic factor glycogen synthase kinase-3-beta (GSK-3-β). Taken together, our work contributed to elucidating the mechanisms of glutamate toxicity in mesencephalic culture and unravelled the signalling pathways associated with rotigotine-induced neuroprotection against glutamate toxicity in primary dopaminergic cultures.
authors.affiliation: Department of Neurology, Technical University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Oster
authors.affiliation: Department of Pathology, Faculty of Veterinary Medicine, Assiut University, 71515 Assiut, Egypt.
authors.forename: Khaled
authors.initials: K
authors.lastname: Radad
authors.affiliation: UCB Pharma SA, Department of Parkinson's Disease and Movement Disorders, CNS Research, Chemin de Foriest, 1420 Braine-l'Alleud, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Scheller
authors.affiliation: Department of Neurology, Technical University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Hesse
authors.affiliation: Department of Neurology, Technical University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Balanzew
authors.affiliation: Department of Neurology, Technical University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Reichmann
authors.affiliation: Department of Neurology, Technical University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address: Gabriele.Gille@uniklinikum-dresden.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gille
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D002118:Calcium; D020746:Calcium Channels, L-Type; D018491:Dopamine Agonists; D018698:Glutamic Acid; D005978:Glutathione; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017448:Receptors, Dopamine D2; D013481:Superoxides; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine
keywords: Glutamate excitotoxicity; Neuroprotection; PI3K/Akt pathway; Parkinson disease; Rotigotine