Objective: To investigate the effects of safinamide (saf) and rasagiline on in vivo glutamate (Glu) release in the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of Parkinson’s disease (PD).

Background: Saf is a novel PD drug with a dual mechanism of action, blockade of MAO-B and inhibition of abnormal Glu release (1). An in vivo microdialysis study in naïve rats (2) showed that saf inhibited veratridine-induced Glu release in subthalamic nucleus (STN 85%), globus pallidus (GP 60%) and substantia nigra reticulata (SNr 85%) but not in dorsolateral striatum (DLS). This effect occurred at a dose of 15 mg/kg giving free plasma concentrations corresponding to the 100 mg human dose and close to the affinity for sodium channels, suggesting it was accomplished via sodium channel blockade. To understand the antiglutamatergic activity of saf and the contribution of MAO-B inhibition to this, in vivo Glu release was studied in 6-OHDA hemilesioned rats in comparison with another MAO-B inhibitor, rasagiline.

Method: A microdialysis probe was implanted in DLS, GP, SNr or STN of 6-OHDA hemilesioned rats. After 24 hours, rats were treated either with a single dose of saf (15 mg/kg i.p.) or saline and 30 min later (plasma Tmax <=60 min) (1) veratridine (10 µM) was perfused through the probe. Rasagiline (0.1 mg/kg, i.p.) was administered 60 min before veratridine (plasma Tmax <=120 min) (3). Both drugs were tested at doses inhibiting MAO-B >50% (1, 4). Glu was measured by HPLC.

Results: In a rat model of PD, saf 15mg/kg inhibited veratridine-evoked Glu release in STN (72%) and GP (80%) but not in DLS and SNr indicating that dopamine depletion alters the response of subthalamo-nigral neurons or terminals to safinamide. Rasagiline did not inhibit Glu release in any of the nuclei.

Conclusion: This study in a rat PD model suggests that MAO-B inhibitors saf and rasagiline differ in their abilities to inhibit depolarization-evoked Glu release in the basal ganglia. The lack of effect of rasagiline suggests that MAO-B inhibition is not involved in the antiglutamatergic activity of saf. The finding that saf inhibits Glu release along the STN-GP axis, which is overactive in PD, suggests this effect might contribute to its observed therapeutic actions of improving motor performance without provoking troublesome dyskinesias.

References: 1) Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, Salvati P, and Fariello RG (2006) Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology 67 (Suppl 2):S18–S23. 2) Morari M, Brugnoli A, Pisanò CA, Novello S, Caccia C, Melloni E, Padoani G, Vailati S, and Sardina M (2018) Safinamide differentially modulates in vivo glutamate and GABA release in the rat hippocampus and basal ganglia. J Pharmacol Exp Ther 364:198–206 3) www.ema.europa.eu/documents/scientific-discussion/azilect-epar-scientific-discussion_en.pdf 4) Youdim, MH, Gross A, and Finberg JPM (2001) Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br. J Pharmacol 132: 500-506.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-safinamide-and-rasagiline-on-in-vivo-glutamate-release-in-6-ohda-hemilesioned-rats/