Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro


Dr A. Nistri, as above.


The neuroprotective agent riluzole is used for the symptomatic treatment of motoneuron disease, which strongly affects the brainstem nucleus hypoglossus. The mechanism of action of riluzole was investigated using, as a model, patch-clamp recording from hypoglossal motoneurons of the neonatal rat brainstem slice preparation. In the presence of riluzole (10 µm), theta-rhythm oscillations evoked by nicotine continued even though the persistent inward current (comprising sodium and calcium components) was halved, but they disappeared when the high frequency of spontaneous glutamatergic currents waned. Riluzole fully inhibited the persistent sodium current and partly depressed a tetrodotoxin (TTX)-insensitive slow current antagonized by Mn2+ or Cd2+. Repetitive firing was inhibited by riluzole without changing single action potentials. In the presence of TTX, riluzole depressed miniature glutamatergic currents occurring at high rate. Synaptic transmission with low release probability became sensitive to riluzole if release was stimulated by high potassium solution. Miniature current frequency was depressed by the N-methyl-d-aspartic acid (NMDA) receptor antagonist d-amino-phosphonovaleriate (50 µm), which fully occluded the action of riluzole. As riluzole is a protein kinase C (PKC) inhibitor, the PKC antagonist chelerythrine (2.5 µm) mimicked the effect of riluzole and prevented it. In summary, riluzole blocked the persistent sodium current fully, and the calcium one partly, plus it decreased glutamatergic transmission probably via inhibition of PKC that regulated presynaptic NMDA receptors having a facilitatory effect on glutamate release. Controlling NMDA receptor function and, thus, excitatory transmitter release via modulation of PKC suggests a novel potential target to contrast glutamate excitotoxicity in this motor nucleus.