Abstract
Safinamide has been recently approved as an add-on to levodopa therapy for Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks sodium channels and modulates glutamate (Glu) 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 Glu 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 Glu and GABA release in the hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide were measured as well. 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 Glu and GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations of 1.89-1.37 µM. This dose attenuated veratridine-stimulated Glu (but not GABA) release in subthalamic nucleus, globus pallidus, and substantia nigra reticulata, but not in striatum. Safinamide was ineffective on spontaneous neurotransmitter release. In vitro, safinamide inhibited sodium channels, showing a greater affinity at depolarized (IC50 = 8 µM) than at resting (IC50 = 262 µM) potentials. We conclude that safinamide inhibits in vivo Glu 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 nondopaminergic mechanism of its action.
Highlights
Safinamide ((S)-(1)-2-[4-(3-fluorobenzyl) oxybenzyl] aminopropanamide methanesulfonate; XADAGO) is a drug originally identified as an anticonvulsant (Fariello et al, 1998; Fariello, 2007) that has recently been approved in European Union and United States as an add-on to a stable dose of levodopa (L-dopa), alone or in combination with other PD medicinal products, for the treatment of patients with mid- to late-stage fluctuating idiopathic Parkinson disease (PD) (Borgohain et al, 2014a,b).Safinamide is a small-molecule drug (Pevarello et al, 1999) that is orally bioavailable (80%–92%) and highly brainpenetrant in rodents and nonhuman primates (Onofrj et al, 2008)
In addition to inhibiting monoamine oxidase type B, it blocks sodium channels and modulates glutamate (Glu) 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 Glu release in vivo and whether this effect is consistent across different brain areas and is selective for glutamatergic neurons
We provide evidence that safinamide differentially inhibits the veratridineinduced Glu and GABA release in the hippocampus and basal ganglia of naïve awake rats, at free brain concentrations effective in blocking voltage-dependent sodium channels
Summary
Safinamide ((S)-(1)-2-[4-(3-fluorobenzyl) oxybenzyl] aminopropanamide methanesulfonate; XADAGO) is a drug originally identified as an anticonvulsant (Fariello et al, 1998; Fariello, 2007) that has recently been approved in European Union and United States as an add-on to a stable dose of levodopa (L-dopa), alone or in combination with other PD medicinal products, for the treatment of patients with mid- to late-stage fluctuating idiopathic Parkinson disease (PD) (Borgohain et al, 2014a,b).Safinamide is a small-molecule drug (Pevarello et al, 1999) that is orally bioavailable (80%–92%) and highly brainpenetrant in rodents and nonhuman primates (Onofrj et al, 2008). Hyperactivity of Glu-releasing neurons of motor cortex and subthalamic nucleus (STN) plays a causative role in this process. Both corticostriatal and corticosubthalamic inputs drive STN hyperactivity, which is a consistent finding across animal models of PD (Bergman et al, 1994; Hassani et al, 1996; Meissner et al, 2005) and PD patients (Magnin et al, 2000; Brown et al, 2001). STN overactivity sustains motor symptoms since it causes overstimulation of nigrothalamic GABA neurons, resulting in thalamic inhibition and impairment of motor planning and execution (Albin et al, 1989; Wichmann et al, 2011). In addition to reinstating nigrostriatal DA transmission, normalizing overactive Glu transmission may prove useful in relieving PD
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