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

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-Daspartate 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.This work was supported by Zambon S.P.A. F.G. and M.M. contributed equally to this work.

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

“…[67][68][69] Finally, a recent study in patients with PD demonstrated that a specific neurophysiological measure reflecting non-NMDA glutamatergic activity in the primary motor cortex is abnormally enhanced in dyskinetic patients, but can be normalized by using safinamide, a drug that inhibits glutamate release by blocking voltage-gated sodium channels. 52,70 Figure 1 shows the main alterations in dopaminergic and glutamatergic synapses in the striatum.…”

The Current Evidence for the Use of Safinamide for the Treatment of Parkinson’s Disease

“…A key driver of this overactivity is represented by a dysregulated neurotransmission mediated by glutamate which is released from cortical and thalamic terminals in the striatum and evokes excitatory synaptic events in SPNs. 49 , 50 Safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which play an important role in the development of dyskinesia. Sciaccaluga et al demonstrated that in experimental animals, safinamide was able to delay the onset of dyskinesia but not their severity once induced.…”

“… 49 Gardoni et al reached a similar conclusion. 50 They investigated the effects of safinamide on the development of dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats and they found that the drug did not halt or delay the priming to levodopa, which underlies the development of dyskinesia, in the rat. However, safinamide did not worsen dyskinesia severity.…”

Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation

“…This might explain why striatal Glu release can sometimes dissociate from AIMs appearance. In fact, in dyskinetic rats chronically treated with the MAO-B and Na V channel inhibitor, safinamide (Gardoni et al , 2018), or intrastriatally perfused with AFDX-116 and PD-102807 (present study) striatal Glu did not rise along with AIMs.…”

“…Our study would point to an inhibitory action of telenzepine at M1 receptors on striato-nigral MSNs. To possibly confirm this view, telenzepine also reduced the LID-associated elevation of striatal Glu release (Brugnoli et al , 2016;Gardoni et al , 2018;Ostock et al , 2011;Paolone et al , 2015). In fact, elevation of striatal Glu release might result from striato-nigral MSNs stimulation leading to activation of cortico-basal ganglia-thalamo-cortical loop (Market al , 2004;Marti et al , 2005) and cortico-striatal terminals (Ostock et al , 2011;Paolone et al , 2015).…”