The Interaction of the Neuroprotective Compounds Riluzole and Phenobarbital with AMPA-Type Glutamate Receptors: A Patch-Clamp Study

Background: Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors is a promising pharmacological strategy in the treatment of neurodegenerative diseases. The aim of the study is to elucidate if there are direct interactions of riluzole and phenobarbital with AMPA-type receptor channels and to determinethe molecular pharmacological mechanisms. Methods: The patch-clamp technique was used combining an ultrafast solution exchange system to investigate the interaction of riluzole and phenobarbital with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). Results: A dose-dependent decrease in the relative peak current amplitude (rAmp) and the relative area-under-the-current curve (rAUC) were found after preincubation with 0.1 mmol/l or higher concentrations of riluzole. Furthermore, in coapplication experiments with GluR2L504Y, the application of 1 or 3 mmol/l riluzole showed a decrease in the current decay time constant, and a reopening current was observed at 3 mmol/l riluzole. Phenobarbital blocks AMPA receptor channels dose-dependently in the coapplication experiments, and reopening currents after removing glutamate and blocker were observed. A slight block effect after preincubation should indicate an additional competitive block effect. Conclusion: Riluzole and phenobarbital modulate AMPA-type receptor channels separately, which could be both characterized as a combination of open-channel block and competitive-block mechanism.