Effects of Retigabine (D‐23129) on Different Patterns of Epileptiform Activity Induced by Low Magnesium in Rat Entorhinal Cortex Hippocampal Slices

Abstract

Summary:Purpose: The objective of this study was to evaluate the effect of a new antiseizure drug, retigabine (D-23129; N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid ethyl ester) on low-Mg*+-induced epileptiform discharges in rat in vitro.Methods: Three types of epileptiform discharges (recurrent short discharges in the hippocampus, seizure-like events, and late recurrent discharges in the entorhinal cortex) were elicited in rat combined entorhinal cortex-hippocampal slices by perfusion with low-Mg*+-artificial cerebrospinal fluid (ACSF). The antiepileptic properties of retigabine were evaluated as effect on the frequency and amplitude of the epileptiform activities as well as time of onset of the effect in the entorhinal cortex (EC) and in hippocampal area CAI (CAI) by using extracellular recording techniques.Results: Retigabine (20 pMj reversibly suppressed the recurrent short discharges otherwise sensitive only to high doses of valproate (VPA) but insensitive to standard antiepileptic drugs (AEDs) in CAI, whereas 10 pM reduced the frequency of discharges by 34 * 18.8%, with no significant effect on the amplitude. In EC, retigabine (50 p M ) reversibly suppressed the seizure-like events, whereas 20 blocked seizure-like events in 71.5% of the slices. The seizure-like events were also sensitive to standard AEDs. Late recurrent discharges in EC that are not blocked by standard AEDs were reversibly suppressed by retigabine (100 pMj, whereas 50 p M reduced the frequency of the discharges by 94.4 c 7.7%, and 20 pM, by 74.2 18.0%, with no significant effect on the amplitude.Conclusions: Retigabine is an effective AED with suppressive effects on recurrent short discharges and on late recurrent discharges normally insensitive to standard AEDs. Key Words: Retigabine-Epileptiform activities-Entorhinal cortex-Hippocampus-Low magnesium.Retigabine (D-23 129), a new antiseizure drug synthesized by ASTA Medica AG (Frankfurt, Germany), is a desazo analogue derivative of flupirtine. Retigabine has been shown to be an effective compound in a large variety of seizure models in vivo and in vitro (1). Retigabine is effective against maximal electroshock and subcutaneous pentylenetetrazol seizures (2,3), in the amygdala kindling model in rats (4), and in two genetic models of epilepsy, the audiogenic seizure DBA/2J mice and the genetically epilepsy-prone rats (5,6). In vitro, reti-

Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

“…Retigabine, a drug that directly augments M-channels, reduces epileptiform activity in several in vitro hippocampal models (Armand et al, 2000;Dost and Rundfeldt, 2000), and is in clinical trials for use in epilepsy (Porter et al, 2007b). After I M blockade, SST inhibition of bursting is reduced by ϳ50%.…”

“…We showed previously that I M is critical in preventing the transition from preseizure interictal epileptiform bursting to ictal seizurelike events in hippocampal slices from both adult and immature rats (Qiu et al, 2007). Furthermore, the drug retigabine, that robustly increases I M , has potent antiepileptic actions in pharmacoresistant animal models (Armand et al, 1999(Armand et al, , 2000. After successful completion of Phase II clinical trials (Porter et al, 2007b), retigabine is currently in Phase III clinical trials for treatment of refractory partial seizures (Porter et al, 2007a,b).…”

KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability

“…Likewise, conditional transgenic suppression of K V 7.2 channels in mouse brain produces an epileptic phenotype (Peters et al, 2005). Finally, blocking K V 7/M channels with linopirdine or XE991 induces epileptiform seizures (Qiu et al, 2007), whereas enhancing K V 7/M channel activity with retigabine exerts an anti-seizure action (Armand et al, 1999(Armand et al, , 2000Dost and Rundfeldt, 2000).…”

The New Anticonvulsant Retigabine Favors Voltage-Dependent Opening of the Kv7.2 (KCNQ2) Channel by Binding to Its Activation Gate

“…None of the anticonvulsants that are in clinical use today has a comparable mechanism of action. RTG is effective in a broad range of epilepsy and seizure models Armand et al, 1999Armand et al, , 2000Dost and Rundfeldt, 2000). In two models of drug-resistant epilepsy, it was the only compound able to antagonize hyperexcitability in a concentration-dependent manner (Armand et al, 1999(Armand et al, , 2000 and was also effective in human brain slices derived from patients with pharmacoresistent epilepsy who underwent epilepsy surgery (Straub et al, 2001).…”