The novel antiepileptic drug carisbamate (RWJ 333369) is effective in inhibiting spontaneous recurrent seizure discharges and blocking sustained repetitive firing in cultured hippocampal neurons

Abstract

SummaryThis study was initiated to investigate effects of the novel neuromodulator carisbamate (RWJ 333369) in the hippocampal neuronal culture model of status epilepticus and spontaneous epileptiform discharges. Whole-cell current clamp techniques were used to determine the effects of carisbamate on spontaneous recurrent epileptiform discharges (SREDs, in vitro epilepsy), depolarization-induced sustained repetitive firing (SRF) and low Mg 2+ -induced continuous high frequency spiking (in vitro status epilepticus). This in vitro model is an important tool to study the effects of anticonvulsant drugs (AEDs) on SREDs that occur for the life of the neurons in culture. Carisbamate dose dependently blocked the expression and reoccurrence of SREDs. The ED 50 value for its antiepileptic effect was 58.75 ± 2.43 μM. Inhibition of SRF is considered a common attribute of many AEDs. Carisbamate (100 μM) significantly decreased SRF in hippocampal neurons. All these effects of carisbamate were reversed during a 5 to 30 min drug washout period. When exposed to low Mg 2+ medium cultured hippocampal neurons exhibit high frequency spiking. This form of in vitro status epilepticus is not effectively blocked by conventional AEDs that are known to be effective in treating status epilepticus in humans. Carisbamate, like phenytoin and phenobarbital, had little or no effect on low Mg 2+ -induced continuous high frequency spiking. These results characterize the effects of carisbamate in the hippocampal neuronal culture model of epileptiform discharges and suggest that the ability of carisbamate to inhibit depolarization-induced SRF may account in part for some of it's anticonvulsant effect.

Saikosaponin a Mediates the Anticonvulsant Properties in the HNC Models of AE and SE by Inhibiting NMDA Receptor Current and Persistent Sodium Current

“…We used neurons 24 h after 3 h exposure to low-Mg 2+ solution in this HNC model of AE, in which condition hippocampal neurons develop SREDs with high-frequency spike firing >3 Hz [25]. The two in vitro models are amenable to experimental manipulation, allow for direct analysis of neurons undergoing SREDs and SE in vitro and are valuable tools for the pharmacological studies on the anticonvulsant effects of various investigational compounds [22], [33].…”

Development of the calcium plateau following status epilepticus: role of calcium in epileptogenesis

“…One study has successfully used pharmacological intervention following injury in the in vitro low Mg 2+ model of SE to prevent the development of SREDs [81]. It was demonstrated that a new anticonvulsant drug [82,83], carisbamate, also exhibited anti-epileptogenic properties in vitro in hippocampal cultures [81]. This means that the drug was able to prevent the development of SREDs when given following in vitro SE and that it did not have to be present in the culture media for the SRED-free activity to persist, differentiating it from most anticonvulsants.…”

One-pot conversion of trimethylsilyl ethers into urethanes using chlorosulfonyl isocyanate: Application to the synthesis of a novel neuromodulator carisbamate

“…1) is a novel neuromodulator with a broad range of anticonvulsant activity (ED 50 5-60 mg/ kg) in rodent seizure models that is under development by Johnson & Johnson Pharmaceutical Research and Development, for the treatment of epilepsy (Deshpande et al, 2008;Rogawski, 2006;Novak et al, 2007;Mannens et al, 2007). Despite its relatively simple structure, there are few synthetic approaches for the target compound reported in the literature.…”