Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease

M. Sciaccaluga; P. Mazzocchetti; G. Bastioli; V. Ghiglieri; A. Cardinale; P. Mosci; C. Caccia; C. Keywood; E. Melloni; G. Padoani; S. Vailati; B. Picconi; P. Calabresi; A. Tozzi

doi:10.1016/j.neuropharm.2020.108024

Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease

M. Sciaccaluga, P. Mazzocchetti, G. Bastioli, V. Ghiglieri, A. Cardinale, P. Mosci, C. Caccia, C. Keywood, E. Melloni, G. Padoani, S. Vailati, B. Picconi, P. Calabresi, A. Tozzi

Istituto San Raffaele Pisana

Research output: Contribution to journal › Article › peer-review

Abstract

Objective: The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (L-DOPA) treatment. Background: Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and L-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of L-DOPA therapy in PD. Methods: Electrophysiological effects of safinamide (1–100 μM) were investigated by patch-clamp recordings in striatal slices of naïve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with L-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the L-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test. Results: Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC₅₀) values in the therapeutic range (3–5 μM). Chronic co-administration of safinamide plus L-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs. Conclusions: Safinamide, at a clinically relevant dose, optimizes the effect of L-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and L-DOPA ameliorates motor deficits.

Original language	English
Number of pages	8
Journal	Neuropharmacology
Volume	170
DOIs	https://doi.org/10.1016/j.neuropharm.2020.108024
Publication status	Published - 2020

Access to Document

10.1016/j.neuropharm.2020.108024

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081406344&doi=10.1016%2fj.neuropharm.2020.108024&partnerID=40&md5=2b62bb71b436eadf0078c754d0ce0ac9

Cite this

Sciaccaluga, M., Mazzocchetti, P., Bastioli, G., Ghiglieri, V., Cardinale, A., Mosci, P., Caccia, C., Keywood, C., Melloni, E., Padoani, G., Vailati, S., Picconi, B., Calabresi, P., & Tozzi, A. (2020). Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease. Neuropharmacology, 170. https://doi.org/10.1016/j.neuropharm.2020.108024

@article{d7a893cea25b4391905bf747773bd29b,

title = "Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease",

abstract = "Objective: The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (L-DOPA) treatment. Background: Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and L-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of L-DOPA therapy in PD. Methods: Electrophysiological effects of safinamide (1–100 μM) were investigated by patch-clamp recordings in striatal slices of na{\"i}ve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with L-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the L-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test. Results: Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC50) values in the therapeutic range (3–5 μM). Chronic co-administration of safinamide plus L-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs. Conclusions: Safinamide, at a clinically relevant dose, optimizes the effect of L-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and L-DOPA ameliorates motor deficits.",

author = "M. Sciaccaluga and P. Mazzocchetti and G. Bastioli and V. Ghiglieri and A. Cardinale and P. Mosci and C. Caccia and C. Keywood and E. Melloni and G. Padoani and S. Vailati and B. Picconi and P. Calabresi and A. Tozzi",

note = "Cited By :1 Export Date: 29 January 2021",

year = "2020",

doi = "10.1016/j.neuropharm.2020.108024",

language = "English",

volume = "170",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease

AU - Sciaccaluga, M.

AU - Mazzocchetti, P.

AU - Bastioli, G.

AU - Ghiglieri, V.

AU - Cardinale, A.

AU - Mosci, P.

AU - Caccia, C.

AU - Keywood, C.

AU - Melloni, E.

AU - Padoani, G.

AU - Vailati, S.

AU - Picconi, B.

AU - Calabresi, P.

AU - Tozzi, A.

N1 - Cited By :1 Export Date: 29 January 2021

PY - 2020

Y1 - 2020

N2 - Objective: The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (L-DOPA) treatment. Background: Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and L-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of L-DOPA therapy in PD. Methods: Electrophysiological effects of safinamide (1–100 μM) were investigated by patch-clamp recordings in striatal slices of naïve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with L-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the L-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test. Results: Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC50) values in the therapeutic range (3–5 μM). Chronic co-administration of safinamide plus L-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs. Conclusions: Safinamide, at a clinically relevant dose, optimizes the effect of L-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and L-DOPA ameliorates motor deficits.

AB - Objective: The aim of the study was to evaluate electrophysiological effects of safinamide on the intrinsic and synaptic properties of striatal spiny projection neurons (SPNs) and to characterize the possible therapeutic antiparkinsonian effect of this drug in dopamine (DA) denervated rats before and during levodopa (L-DOPA) treatment. Background: Current therapeutic options in Parkinson's disease (PD) are primarily DA replacement strategies that usually cause progressive motor fluctuations and L-DOPA-induced dyskinesia (LIDs) as a consequence of SPNs glutamate-induced hyperactivity. As a reversible and use-dependent inhibitor of voltage-gated sodium channels, safinamide reduces the release of glutamate and possibly optimize the effect of L-DOPA therapy in PD. Methods: Electrophysiological effects of safinamide (1–100 μM) were investigated by patch-clamp recordings in striatal slices of naïve, 6-hydroxydopamine (6-OHDA)-lesioned DA-denervated rats and DA-denervated animals chronically treated with L-DOPA. LIDs were assessed in vivo with and without chronic safinamide treatment and measured by scoring the L-DOPA-induced abnormal involuntary movements (AIMs). Motor deficit was evaluated with the stepping test. Results: Safinamide reduced the SPNs firing rate and glutamatergic synaptic transmission in all groups, showing a dose-dependent effect with half maximal inhibitory concentration (IC50) values in the therapeutic range (3–5 μM). Chronic co-administration of safinamide plus L-DOPA in DA-denervated animals favored the recovery of corticostriatal long-term synaptic potentiation (LTP) and depotentiation of excitatory synaptic transmission also reducing motor deficits before the onset of LIDs. Conclusions: Safinamide, at a clinically relevant dose, optimizes the effect of L-DOPA therapy in experimental PD reducing SPNs excitability and modulating synaptic transmission. Co-administration of safinamide and L-DOPA ameliorates motor deficits.

U2 - 10.1016/j.neuropharm.2020.108024

DO - 10.1016/j.neuropharm.2020.108024

M3 - Article

VL - 170

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -

Effects of safinamide on the glutamatergic striatal network in experimental Parkinson's disease

Abstract

Access to Document

Fingerprint

Cite this