RT Journal Article
SR Electronic
T1 Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 442
OP 451
DO 10.1124/jpet.118.251645
VO 367
IS 3
A1 F. Gardoni
A1 M. Morari
A1 J. Kulisevsky
A1 A. Brugnoli
A1 S. Novello
A1 C. A. Pisanò
A1 C. Caccia
A1 M. Mellone
A1 E. Melloni
A1 G. Padoani
A1 V. Sosti
A1 S. Vailati
A1 C. Keywood
YR 2018
UL http://jpet.aspetjournals.org/content/367/3/442.abstract
AB 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.