The interaction of the neuroprotective compounds riluzole and phenobarbital with AMPA-type glutamate receptors: a patch-clamp study.
BACKGROUND
Blockade of alpha-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.


CONCLUSIONS
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.
Jin
Ling-Jing
LJ
Neurological Department of the Medical School Hannover and Center of Systems Neuroscience Hannover, Hannover, Germany. lingjingjin @ hotmail.com
Schlesinger
Friedrich
F
Song
Yun-Ping
YP
Dengler
Reinhard
R
Krampfl
Klaus
K
D019540:Area Under Curve; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019782:Riluzole / Q000008:administration & dosage / Q000494:pharmacology*
D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D019782:Riluzole; D010634:Phenobarbital