Abstract
Safinamide has been recently approved as add-on to levodopa therapy in Parkinson's disease. In addition to inhibiting monoamine oxidase-type B, it also blocks sodium channels and modulates glutamate release in vitro. Since this property might contribute to the therapeutic action of the drug, we undertook the present study to investigate whether safinamide inhibits glutamate release also in vivo, and whether this effect is consistent across different brain areas and is selective for glutamatergic neurons. To this aim, in vivo microdialysis was used to monitor the spontaneous and veratridine-induced glutamate and GABA release in the hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide were measured along. To shed light on the mechanisms underlying the effect of safinamide, sodium currents were measured by patch-clamp recording in rat cortical neurons. Safinamide maximally inhibited the veratridine-induced glutamate and GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations of 1.89-1.37 µM. This dose attenuated the veratridine-stimulated glutamate (but not GABA) release also in subthalamic nucleus, globus pallidus and substantia nigra reticulata, but not striatum. Safinamide was ineffective on spontaneous neurotransmitter release. In vitro, safinamide inhibited sodium channels, showing greater affinity at depolarized (IC50=8 µM) than resting (IC50=262 µM) potentials. We conclude that safinamide inhibits in vivo glutamate release from stimulated nerve terminals likely via blockade of sodium channels at subpopulations of neurons with specific firing patterns. These data are consistent with the anticonvulsant and antiparkinsonian actions of safinamide, and provide support for the non-dopaminergic mechanism of its action.
- The American Society for Pharmacology and Experimental Therapeutics