Kainate‐induced currents in rat cortical neurons in culture are modulated by riluzole

Abstract

The action of the neuroprotective and anticonvulsant agent riluzole on kainate-induced currents was studied in rat cortical neurons in primary culture by using the whole-cell configuration of the patch-clamp technique. Kainate elicited macroscopic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive inward currents in all the patched cells and the amplitude of the current was concentration-dependent (EC50= 106 microM). Riluzole decreased the inward currents induced by 100 microM kainate at all holding potentials and the reduction was dose-dependent (IC50= 101 microM). The maximal response to kainate decreased in the presence of 50 microM riluzole, without changing its EC50, indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control conditions and during riluzole was a linear function of the membrane potential and the reversal potential of the currents was not significantly different in the two experimental conditions. Instead, the total conductance of the cell membrane for the currents induced by 100 microM kainate was significantly reduced in the presence of 50 microM riluzole (P < 0.05). The analysis of the kainate membrane current noise performed under control conditions and during perfusion of 100 microM riluzole revealed that riluzole reduced the probability of kainate-activated ionic channels to be in the open state. Conversely, the unitary conductance of channels, as well as their characteristic time constant, seemed to be unchanged. These results reveal an additional mechanism by which riluzole can interact with glutamatergic neurotransmission and provides further support for the idea that riluzole may prove beneficial in the treatment of central nervous system injuries involving the excitotoxic actions of glutamate.

Persistent Sodium Currents Participate in Fictive Locomotion Generation in Neonatal Mouse Spinal Cord

“…A major issue of the use of riluzole is its specificity: other studies have shown that riluzole also blocks potassium channels (Zona et al, 1998;Duprat et al, 2000;Cao et al, 2002;Ahn et al, 2005), calcium channels (Huang et al, 1997), and glutamatergic synaptic transmission (Zona et al, 2002;Albo et al, 2004). However, it is unlikely that the effects of riluzole reported here are attributable to these nonspecific effects.…”

Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

“…It is worth noting that miniature EPSC amplitude reduction by riluzole, although statistically significant, was small, suggesting that direct modulation of synaptically activated glutamate receptors by riluzole may be a minor contributor to reduction of synaptic transmission; in contrast, while the reduction of glutamate receptor currents by riluzole was greater, the method of application used here is more likely to activate predominantly extrasynaptic glutamate receptors (Townsend et al 2003). In addition, although some studies have reported that electrophysiological responses to glutamate receptor ligands were inhibited by riluzole (Centonze et al 1998;Debono et al 1993;Zona et al 2002), this inhibition may be via indirect modulation of receptor function, as a number of radioligand binding studies have consistently failed to find any interaction of riluzole with the NMDA, glycine, or phencyclidine binding sites of NMDA glutamate receptors or the ligand binding site of non-NMDA glutamate receptors (Benavides et al 1985;Debono et al 1993;He et al 2002).…”

Direct Effects of Riluzole on 5-Hydroxytryptamine (5-HT)3 Receptor–Activated Ion Currents in NCB-20 Neuroblastoma Cells

“…It has been reported that riluzole increased the time constant of fast desensitization and decreased the time constant of slow desensitization and steady-state current of GABA A and glycine receptors (5). Also, riluzole decreased the activity of AMPA receptors and the kainate-induced currents (4,7). These results indicate that riluzole inhibits neuronal excitability and protects against excitotoxicity.…”