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.