Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate‐induced Epilepsy

Grabenstatter, Heidi L.; Ferraro, Damien; Williams, Philip A.; Chapman, Phillip L.; Dudek, F. Edward

doi:10.1111/j.0013-9580.2005.13404.x

Cited by 90 publications

(88 citation statements)

References 33 publications

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“…In addition, carisbamate reduced the frequency of action potentials generated during depolarization-induced SRF. Our results are consistent with other studies that have demonstrated antiepileptic properties of carisbamate in various in vivo models of seizures (Bialer et al, 2007;Francois et al, 2005;Grabenstatter and Dudek, 2004;Nehlig et al, 2005;Rogawski, 2006;White et al, 2006). While the exact mechanism of action of carisbamate is not known and is being actively investigated, the ability of carisbamate to inhibit depolarization-induced SRF may account in part for some of the anticonvulsant effects of carisbamate.…”

Section: Discussionsupporting

confidence: 93%

“…Carisbamate has been evaluated as a novel AED and has demonstrated antiepileptic activity in a variety of in vivo seizure models including hippocampal and corneal kindling (Bialer et al, 2007;Rogawski, 2006) and the GAERS model of absence epilepsy . It also inhibits spontaneous recurrent seizures after kainate induced epilepsy (Grabenstatter and Dudek, 2004) and delays or prevents Li-Pilocarpine (Francois et al, 2005) induced epilepsy. Carisbamate is also anticonvulsant against bicuculline and picrotoxin induced seizures and in pentylenetetrazole and maximal electroshock induced seizure models (Bialer et al, 2007;Rogawski, 2006;White et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…Systemic administration of repeated, low doses of KA, results in a pattern of hippocampal degeneration similar to that observed after a single, high dose of kainate, with improved survival, and increased percentage of animals showing spontaneous seizures [20,23,24,33]. After KA administration, during the acute phase that may last up to 10 hours, the animal presents immobility, facial clonus, sniffing, wet dog shakes, and stage III to V seizures (rated according to Racine's scale), all leading to status epilepticus (SE).…”

Section: Introductionmentioning

confidence: 71%

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

Castillo

Mendoza-Trejo

Aguilar

et al. 2008

Behavioural Brain Research

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We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [5] in an animal model. In the present study, recurrent NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O Cl4 transplants, the death rate was reduced to less than 20%. The M213-2O Cl4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67cDNA, as well as increased GABA levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

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“…carisbamate significantly reduced the frequency of spontaneous seizures (74% reduction at 30 mg/kg, P Ͻ 0.0001). 3 Furthermore, carisbamate was more effective than topiramate in completely suppressing spontaneous recurrent seizures in a larger fraction of the rats studied (i.e., seven of eight rats completely suppressed at 30 mg/kg i.p. versus one of eight rats completely suppressed at 100 mg/kg i.p., respectively).…”

Section: Pharmacologymentioning

confidence: 86%

Carisbamate (RWJ-333369)

et al. 2007

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Summary: Carisbamate (RWJ-333369) is a novel neuromodulator, initially developed by SK Biopharmaceuticals (Fairlawn, NJ), under development by Johnson & Johnson Pharmaceutical Research and Development (La Jolla, CA). Carisbamate displays high potency in a broad range of rodent seizure models at doses well below those that produce CNS toxicity. Its mechanism of action has not been elucidated. Acute and chronic nonclinical toxicological studies have not revealed any significant abnormalities other than dose-related CNS toxicity. It is extensively metabolized, chiefly through glucuronidation and oxidation of the aliphatic side chain. There is little evidence of CYP metabolism. It has linear pharmacokinetics. Its clearance is increased by carbamazepine and to a lesser degree by oral contraceptives. Carisbamate slightly increases the clearance of valproic acid and lamotrigine. The most common adverse events in humans are headaches, dizziness, and somnolence, generally mild to moderate, occurring at doses of 1000 mg/day or more. A recently completed phase 2 study for adjunctive use in partial onset seizures showed efficacy at a dose that was well tolerated.

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Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate‐induced Epilepsy

Cited by 90 publications

References 33 publications

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

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

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

Carisbamate (RWJ-333369)

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