Efficacy of Topiramate Against Soman Intoxication: Attenuation of Seizures Without Neuroprotection

The possibility of mass exposure to nerve agents is at present a major concern. There is, therefore, an urgent need for the development of medical countermeasures against exposure, that are effective as well as safe. A major clinical symptom of nerve agent exposure is intense seizure activity/status epilepticus (SE). Control of seizures is of paramount importance in order to prevent death, or brain damage which can have long-term neurobehavioral consequences. Although the discovery of novel drugs that can block nerve agent-induced seizures is necessary, testing known anticonvulsants that are already approved by the FDA may result in an effective antidote that can be immediately available, and can provide at least a short-term solution. We recently found that LY293558, an antagonist of GluK1 and AMPA receptors, stops soman-induced seizures and protects limbic and cortical regions from soman-induced neuropathological alterations. Topiramate, an anticonvulsant that is already approved by the FDA, suppresses seizures via a number of mechanisms, including blockade of GluK1 receptors, but its effectiveness against nerve agents has not been tested. Therefore, in the present study we investigated the anticonvulsant and neuroprotective efficacy of topiramate against the nerve agent soman. Administered at 30 min or 60 min after soman injection to rats, topiramate prevented mortality and suppressed seizures, but had minimal neuroprotective effects, studied in limbic and cortical regions, one day after exposure. Neurodegeneration, as determined by Fluoro-Jade C staining, was reduced in the entorhinal cortex when topiramate was administered at 30 min after soman exposure, but it was higher in a neocortical area when topiramate was administered at 60 min post-exposure. Neuronal loss in the basolateral nucleus of the amygdala, determined by design-based stereology on Nissl-stained sections, was not reduced by topiramate. Thus, topiramate can treat some symptoms of soman toxicity, but is unlikely to protect against soman-induced brain damage.