Two new actions of topiramate: inhibition of depolarizing GABA(A)-mediated responses and activation of a potassium conductance.
Topiramate (TPM) is an antiepileptic with several proposed mechanisms of action including the inhibition of carbonic anhydrase (CA). Since the activity of this enzyme is essential for the generation of GABA(A)-mediated depolarizing responses, which appears to participate in epileptogenesis, we investigated whether TPM could inhibit such a response in rat hippocampal slices using intracellular recordings. Bath perfusion of TPM (20 and 100 microM) reversibly reduced the GABA(A)-mediated depolarizing responses evoked by either synaptic stimulation (GDPSPs) or by pressure application of GABA, but did not modify the GABA(A)-mediated hyperpolarizing postsynaptic potentials. TPM (20 microM) shifted the reversal potential for the GDPSP by -10 mV. Unexpectedly, TPM also induced a steady membrane hyperpolarization associated with a reduction in the input resistance of the cell. This effect was insensitive to tetrodotoxin, and to GABA(A) and GABA(B) receptor antagonists, but was blocked by barium (1 mM). Notably, when the extracellular concentration of K(+) was varied the reversal potential shifted as predicted by the Nernst potential for K(+). Acetazolamide (20 microM), another CA inhibitor, elicited similar effects to those reported here for TPM and occluded the hyperpolarization evoked by TPM. The results of this study support the concept that inhibition of carbonic anhydrase in neurons contributes to the anticonvulsant activity of TPM.
Herrero
Ana I
AI
Servicio de Neurobiología, Depto. de Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain.
Del Olmo
Nuria
N
González-Escalada
José R
JR
Solís
José M
JM
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism; D004558:Electric Stimulation; D004594:Electrophysiology; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010852:Picrotoxin / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000927:Anticonvulsants; D002256:Carbonic Anhydrases; D005632:Fructose; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D010852:Picrotoxin; D015221:Potassium Channels; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid