Flufenamic acid suppresses epileptiform activity in hippocampus by reducing excitatory synaptic transmission and neuronal excitability.
OBJECTIVE
In this study, we explore the antiepileptic effects of flufenamic acid (FFA) in order to identify the cellular mechanisms that underlie the potential anticonvulsant properties of this nonsteroidal antiinflammatory compound.


METHODS
The mechanisms of FFA action were analyzed using an in vitro model in which epileptiform activity was induced in hippocampal slices by perfusion with 100 microm 4-aminopyridine (4-AP) added to a modified Mg(2+)-free solution. The activity of CA1 pyramidal neurons as well as the synaptic connection between CA3 and CA1 was monitored using extracellular and patch-clamp recordings.


RESULTS
Epileptiform activity was suppressed in hippocampal neurons by FFA at concentrations between 50 and 200 microm. Glutamatergic excitatory synaptic transmission was diminished by FFA without modifying recurrent gamma-aminobutyric acid (GABA)ergic synaptic inhibition. Several lines of evidence indicated that FFA did not decrease neurotransmitter release probability, implicating a postsynaptic mechanism of action. FFA also potently reduced neuronal excitability, but did not alter the amplitude, duration, or undershoot of action potentials.


CONCLUSIONS
Our results suggest that FFA exerts an anticonvulsive effect on hippocampal pyramidal neurons by simultaneously decreasing glutamatergic excitatory synaptic activity and reducing neuronal excitability. Therefore, our study provides experimental evidence that FFA may represent an effective pharmacologic agent in the treatment of epilepsy in the mammalian central nervous system.
Fernández
Miriam
M
Laboratory of Neurophysiology and Synaptic Plasticity, Regional Center for Biomedical Research (CRIB), University of Castilla-La Mancha, Albacete, Spain.
Lao-Peregrín
Cristina
C
Martín
Eduardo D
ED
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005439:Flufenamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D005439:Flufenamic Acid; D015761:4-Aminopyridine