Characterization of the interaction between fenamates and hippocampal neuron GABA(A) receptors.
Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1-100 microM) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the most potent and efficacious and was found to shift the GABA dose-response curve to the left without effect on the maximum amplitude or the GABA Hill Slope. The modulation of GABA receptors by MFA was not reduced in the presence of the benzodiazepine antagonist, flumazenil (10 microM) and was moderately voltage-dependent. MFA at concentrations >or=10 microM evoked dose-dependent currents in the absence of GABA. These currents were potentiated by diazepam (1 microM) and blocked by bicuculline (10 microM). The MFA (50 microM) current-voltage relationship and reversal potential were similar to that evoked by GABA. MFA (1-100 microM) had no effects on sub-maximal glycine, glutamate or NMDA evoked currents. These data show that fenamate NSAIDs are a highly effective class of GABA(A) receptor modulator and activators.
Coyne
Leanne
L
TJ Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, USA.
Su
Jiping
J
Patten
Debra
D
Halliwell
Robert F
RF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D054361:Fenamates / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054361:Fenamates; D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D003975:Diazepam