Frequency‐dependent inhibition of neuronal activity by topiramate in rat hippocampal slices

Abstract

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 e cacy 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 e ect on both ®eld excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequency from 0.05 ± 0.2 Hz, topiramate signi®cantly decreased the slope of fEPSP and the amplitude of PS in a concentration-dependent manner. The amplitude of presynaptic ®ber volley was also reduced. 3 Topiramate did not a ect the magnitude of paired-pulse inhibition and monosynaptically evoked inhibitory postsynaptic potentials (IPSPs). 4 Sustained repetitive ®ring was elicited by injection of long duration (500 ms) depolarizing current pulses (500 ± 800 pA). Superfusion with topiramate signi®cantly reduced the number of action potentials evoked by a given current pulse. 5 After blockade of GABA receptors by bicuculline, burst ®ring 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 e ect 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 e cacy of topiramate.

Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

“…The anticonvulsant effects of TPM in seizure models are attributed primarily to its actions on sodium channels (15)(16)(17)30,31). The voltage-dependent sodium conductances are modulated at TPM concentrations of M that overlap the estimated CSF TPM concentrations in patients taking 300-700 mg daily (Fig.…”

“…Figure 5 shows the estimated human brain and CSF TPM concentrations with the first dose and daily doses. Studies in rodent brain-slice preparations and cell-culture systems suggest that the effects of TPM on voltage-sensitive calcium and sodium channels, kainate receptors, and chloride channels have threshold concentrations of ∼10 M (14)(15)(16)(17)30,31). Starting doses of 400-600 mg would appear to be needed to achieve this brain concentration in adults.…”

“…Brain TPM concentrations for rodent models were adapted from the literature (15,30,33). Concentrations for the effects of TPM on voltage-sensitive calcium and sodium channels, kainate receptors, chloride channels, and electrophysiology responses measured in rodent brain-slice preparations and cell-culture systems are indicated by dashed lines (14)(15)(16)(17)30,31). Based on our data, the GABAergic system in patients is stimulated by maximal plasma concentrations (C max ) <5 µM and brain TPM concentrations of <2 µM.…”

Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission

“…Indeed, standard and investigational moodstabilisers also target directly or indirectly excitatory neurotransmission (Sanacora et al, 2008). In addition to presynaptic blockade of glutamate release (Anand et al, 2000;Cunningham et al, 2003;Kang et al, 2005;Leach et al, 1991;Wu et al, 1998;Zona and Avoli, 1997), mood-stabilisers affect other components of (tripartite) glutamatergic synapse and control glutamate effects in synaptic cleft or at Fig. 4.…”

Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder

“…Topiramate has a broad spectrum of pharmacologic properties, including Na + channel blockade [7-11], inhibition of some high voltage-activated Ca 2+ channels [12], enhanced γ-aminobutyric acid (GABA) neuroinhibition at novel GABA A receptors [13,14], glutamate inhibition at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors [15,16], and promotion of protein phosphorylation of neuronal conductance channels [15]. These properties, together with inhibitory activity in animal kindling models [17,18], suggest that topiramate may have therapeutic potential in PTSD.…”