Objective: The effect of safinamide (saf) on the electrical membrane properties and both excitatory and inhibitory synaptic transmission of striatal spiny projection neurons (SPNs) was investigated in a rat model of Parkinson’s disease (PD).

Background: PD is characterized by degeneration of nigrostriatal dopaminergic neurons. Dopamine (DA), released by the substantia nigra pars compacta, modulates the excitability and synaptic transmission of striatal SPNs. DA denervation impairs this modulation and causes changes in the firing frequency and glutamate-induced hyperactivity of SPNs, which are implicated in motor complications associated with long term levodopa (L-DOPA) therapy. As a reversible inhibitor of voltage-gated sodium channels, saf can reduce glutamate release and potentially counteracts abnormal SPN responses caused by DA-denervation.

Method: Saf (1-100µM) effects on SPN electrical membrane properties and on spontaneous and evoked synaptic transmission, were investigated by patch-clamp recordings in striatal slices of naïve rats and 6-hydroxydopamine (6-OHDA) DA-denervated rats. A group of 6-OHDA rats received a chronic in vivo treatment with 6mg/Kg L-DOPA+12mg/Kg benserazide in the presence or absence of saf (15mg/kg, 30 min before the administration of L-DOPA), once a day for 3 weeks.

Results: In vitro saf reduced the firing rate and frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSC and sIPSC) of SPNs in both naïve and DA-denervated rats, with comparable IC50 values (firing rates: 3.5 and 5.5 µM, respectively; sEPSC: 2.4 and 2.5 µM, respectively; sIPSC: 4.4 and 5 µM), in the human therapeutic range (3-5 µM). Moreover, saf reduced the evoked EPSC and IPSC amplitude in a dose-dependent manner (EPSC: IC50 =16 and 20 µM, respectively for naïve and 6-OHDA rats). Chronic in vivo treatment with saf (15mg/kg, i.p. injection once a day for 3 weeks), 30 min before the administration of L-DOPA, also significantly reduced the firing rate of SPNs by 43% respect to L-DOPA treatment alone (p<0.05).

Conclusion: Saf, at clinically relevant concentrations, reduces SPN membrane excitability and modulates synaptic transmission. These actions might contribute to the beneficial motor effects of saf in PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safinamide-reduces-membrane-excitability-and-synaptic-transmission-of-striatal-spiny-projection-neurons-in-a-rat-model-of-parkinsons-disease/