Epilepsy In Vitro Disease Model for Epileptogenesis

Epilepsy is one of the most common neurological disorders worldwide. The term epilepsy comprises a variety of different syndromes which all have the occurrence of recurrent unprovoked seizures in common.

Although most patients become seizure-free on antiepileptic drugs, about 20-30% of patients continue to have seizures. For those patients no adequate pharmacological treatment is available yet.

Current treatment of epilepsy with drugs relies on symptomatic control of seizures. However, epilepsy cannot be cured with medication, because the mechanisms underlying epileptogenesis are still largely unknown.

NeuroProof has developed an in vitro screening assay to investigate the effects of new classes of antiepileptic compounds. Neuronal networks of embryonic hippocampus neurons grow on MEA chips and develop spontaneous ictal-like activity under certain culture conditions. This assay mimics epileptogenic effects. The activity is characterized by synchronous burst events with a duration of >5 s. Anticonvulsive compounds such as carbamazepine and valproic acid have been shown to resolve these long burst events, while duration of bursts from healthy hippocampus networks are not affected by these compounds.

Image: Screenshot from hippocampus network revealing burst events with >10 s burst duration. Arrows indicate short synchronous burst events preceding the ictal discharges.

The NeuroProof technology can also help to understand pro-convulsive compounds such as picrotoxin that induce ictal-like discharges in network activity of frontal cortex cultures. During these ictal discharges bursts are arranged into longer duration burst events that intermit frontal cortex activity.

Using our classification analysis we can predict excitatory or only pro-convulsive potential of test compounds.

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Image: Native activity of frontal cortex cultures is characterized by highly synchronous burst events. After application of 5 µM picrotoxin bursts occur to be arranged in longer burst events (middle). In contrast, NMDA which excites FC networks simply increases burst rate, but burst duration does not significantly changes.

NeuroProof offers specific in vitro assays for drug discovery in epilepsy. Human iPSC derived neurons can also be used in these assays to increase translation into humans.

Using our classification analysis we can predict excitatory or only pro-convulsive potential of test compounds. Here we refer to our side effect asays.