Frequency-dependent inhibition of neuronal activity by topiramate in rat hippocampal slices.
1. Topiramate is a structurally novel anticonvulsant which was recently approved for adjunctive therapy in partial and secondarily generalized seizures. The present study was aimed at elucidating the mechanisms underlying the anticonvulsant efficacy of topiramate using intra- and extracellular recording techniques in the in vitro hippocampal slices. 2. When stimuli were delivered every 20 s, topiramate had no measurable effect on both field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequency from 0.05-0.2 Hz, topiramate significantly decreased the slope of fEPSP and the amplitude of PS in a concentration-dependent manner. The amplitude of presynaptic fiber volley was also reduced. 3. Topiramate did not affect the magnitude of paired-pulse inhibition and monosynaptically evoked inhibitory postsynaptic potentials (IPSPs). 4. Sustained repetitive firing was elicited by injection of long duration (500 ms) depolarizing current pulses (500-800 pA). Superfusion with topiramate significantly reduced the number of action potentials evoked by a given current pulse. 5. After blockade of GABA receptors by bicuculline, burst firing which consisted of a train of several spikes riding on a large depolarizing wave termed paroxysmal depolarizing shift (PDS) was recorded. Application of topiramate reduced the duration of PDS and later spikes with less effect on the initial action potential. 6. These results suggest that frequency-dependent inhibition of neuronal activity due to blockade of Na+ channels may account largely for the anticonvulsant efficacy of topiramate.
Wu
S P
SP
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan City, Taiwan.
Tsai
J J
JJ
Gean
P W
PW
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009407:Nerve Block; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D005680:gamma-Aminobutyric Acid