In vitro activity: Riluzole inhibits the release of glutamic acid from cultured neurons, and from brain slices. These effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Electrophysiologic experiments performed on isolated excitatory amino acid receptors expressed in the Xenopus oocyte have revealed that Riluzole inhibits currents evoked by N-methyl-D-aspartate (NMDA) (IC50 = 18 μM) and kainic acid (IC50 = 167 μM). Riluzole has been shown to stabilize inactivated sodium channels in frog sciatic nerve, in rat cerebellar granule cells, and on recombinant rat sodium channels expressed in Xenopus oocytes (Ki = 0.2 μM). Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of NMDA receptors. Tiluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.

Cell Assay: In HEKGLT1, HEKGLAST or HEKEAAC1 cells, riluzole increased Na+-dependent uptake in a dose-dependent manner, with significant effects at concentrations as low as 0.01–0.1 μM and the highest effect at 100 μM. The increase in glutamate uptake induced by 100 μM riluzole was similar in all cell lines (+27% in HEKGLAST, +38% in HEKGLT1, +39% in HEKEAAC1). Higher riluzole concentrations (300 and 1000 μM) were toxic, since at the end of experiments the majority of cells were floating, and specific and non-specific glutamate uptake were reduced by more than 50%.

Neurology. 1996 Dec;47(6 Suppl 4):S233-41; Naunyn-Schmiedeberg's Archives of Pharmacology