Objective: To test the effect of safinamide, at the doses of 50 and 100 mg/day, on primary motor cortex (M1) excitability and glutamatergic neurotransmission in patients with Parkinson’s Disease (PD).

Background: Safinamide is a recently approved add-on treatment for patients with PD and ‘OFF episodes’. It exerts a dual mechanism of action: selective MAO-B inhibitor and anti-glutamatergic effect via blockade of voltage-gated sodium channels. However, the latter mechanism of action has never been demonstrated in humans so far.

Methods: Sixteen patients with PD and 16 healthy subjects (HS) were enrolled in the study, which was approved by the Ethical Review Board. Each patient underwent three separate experimental sessions: before taking safinamide (T0), after 2 weeks of safinamide 50 mg/day (T1) and after 2 weeks of safinamide 100 mg/day (T2). In each session, patients were tested in a practical state of OFF and ON (under their best L-Dopa treatment). The clinical assessment consisted of UPDRS-III and UDysRS-III, whereas Transcranial Magnetic Stimulation protocols included Input/output (I/O) curve, Intracortical facilitation (ICF) and Short-interval intracortical facilitation (SICF) in order to assess M1 glutamatergic neurotransmission. Moreover, Short-interval intracortical inhibition (SICI) was evaluated to explore M1 GABA-A neurotransmission.

Results: Safinamide significantly improved UPDRS-III at T1 and T2, both in patients OFF and ON state of therapy, and left the UDysRS-III score unchanged. The slope of the I/O curve was steeper and SICF was increased in patients compared to HS, whereas SICI and ICF were similar in the two groups. The I/O curve, SICI and ICF were all unchanged in patients taking and not taking safinamide at T1 and T2, both in OFF and ON state. Safinamide decreased SICF, in patients taking both 50 and 100 mg/day even though the effect was prominent at 100 mg/day. Finally, there was a significant correlation between changes in UDysRS-III score and changes in SICF at T2.

Conclusions: We provide the first evidence of anti-glutamatergic effect of safinamide in M1, in patients with PD. The effect of safinamide, observed only on SICF, points to a modulation of glutamatergic transmission restricted to specific M1 circuits. The results support the hypothesis of a frequency-dependent effect of safinamide (modulation of neuronal firing) rather than reflecting overall changes in M1 glutamatergic transmission.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/anti-glutamatergic-effect-of-safinamide-in-parkinsons-disease-a-tms-study/