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J Pharmacol Exp Ther. 2018 Dec;367(3):442-451. doi: 10.1124/jpet.118.251645. Epub 2018 Oct 5.

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia.

Author information

1
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (F.G., M.Me.); Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy (M.Mo., A.B., S.N., C.A.P.); Sant Pau Institute of Biomedical Research, Barcelona, Spain (J.K.); Universitat Autònoma de Barcelona, Universitat Oberta de Catalunya, Barcelona, Spain (J.K.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain (J.K., V.S.); Department of R&D, Zambon SpA, Bresso, Milan, Italy (C.C., E.M., G.P., S.V., C.K.); and Neuropsychopharmacology Laboratory, Movement Disorders Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (V.S.) fabrizio.gardoni@unimi.it.
2
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy (F.G., M.Me.); Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy (M.Mo., A.B., S.N., C.A.P.); Sant Pau Institute of Biomedical Research, Barcelona, Spain (J.K.); Universitat Autònoma de Barcelona, Universitat Oberta de Catalunya, Barcelona, Spain (J.K.); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain (J.K., V.S.); Department of R&D, Zambon SpA, Bresso, Milan, Italy (C.C., E.M., G.P., S.V., C.K.); and Neuropsychopharmacology Laboratory, Movement Disorders Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (V.S.).

Abstract

Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia.

PMID:
30291173
DOI:
10.1124/jpet.118.251645

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