Session Time: 1:45pm-3:15pm
Location: Hall 3FG
Objective: To evaluate whether safinamide inhibits in vivo glutamate (Glu) release in a rodent model of Parkinson’s disease (PD), i.e. the 6-hydroxydopamine (6-OHDA) hemilesioned rat.
Background: Safinamide is a novel drug endowed with a dual mechanism of action, i.e. blockade of MAO-B and inhibition of glutamate release (Caccia et al., Neurology 67, Suppl 2, S17-S23, 2006), approved as add-on to levodopa therapy in Parkinson’s disease (PD). In naïve rats, safinamide, likely via use-dependent sodium channel blockade, inhibited in vivo Glu release from stimulated nerve terminals in the subthalamic nucleus (STN) and its projection areas, globus pallidus (GP) and substantia nigra reticulata (SNr), but not dorsolateral striatum (DLS). The effective free brain concentration range was close to the affinity value for sodium channels (Morari et al., J Pharmacol Exp Ther 364, 198-206, 2018) and overlapped that estimated in PD patients at the therapeutic dose of 100 mg.
Methods: One microdialysis probe was implanted in the DA-depleted DLS or GP, SNr and STN of 6-OHDA hemilesioned rats. Rats were treated with safinamide (15 mg/kg i.p.) and, 30 min later, reverse dialysis of veratridine (10 microM) was performed for 30 min in each area. Control rats were treated with saline. Glu was measured by HPLC coupled with fluorometric detection.
Results: In control rats, veratridine caused a transient, about 2-fold rise of Glu levels in all nuclei examined. Safinamide differentially inhibited the veratridine-evoked Glu release with almost complete inhibition in STN and GP but no effect in DLS and SNr. Safinamide did not affect spontaneous GLU efflux.
Conclusions: This study provides the first evidence that safinamide inhibits the stimulus-evoked Glu release in the DA-depleted rat basal ganglia, namely the GP and STN areas in which increased glutamatergic activity is known to produce PD motor complications. This suggests that the therapeutic effects of the drug on PD symptoms may, in part, be mediated by a reduction in Glu levels in GP and STN. The different response to safinamide in DA depleted SNr, also involved in the control of motor symptoms, needs to be further investigated. These data support the notion that the dual mechanism of action of safinamide is relevant in PD.
To cite this abstract in AMA style:G. Padoani, S. Novello, C. Pisanò, C. Caccia, E. Melloni, S. Vailati, C. Keywood, M. Morari. Safinamide inhibition of in vivo glutamate release in a rat model of Parkinson’s Disease [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/safinamide-inhibition-of-in-vivo-glutamate-release-in-a-rat-model-of-parkinsons-disease/. Accessed December 7, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/safinamide-inhibition-of-in-vivo-glutamate-release-in-a-rat-model-of-parkinsons-disease/