BICS01 Mediates Reversible Anti-seizure Effects in Brain Slice Models of Epilepsy

Drug-resistant epilepsy remains a significant clinical and societal burden, with one third of people with epilepsy continuing to experience seizures despite the availability of around 30 anti-seizure drugs (ASDs). Further, ASDs often have substantial adverse effects, including impacts on learning and memory. Therefore, it is important to develop new ASDs, which may be more potent or better tolerated. Here, we report the preliminary preclinical evaluation of BICS01, a synthetic product based on a natural compound, as a potential ASD. To model seizure-like activity in vitro, we prepared hippocampal slices from adult male Sprague Dawley rats, and elicited epileptiform bursting using high extracellular potassium. BICS01 (200 mu M) rapidly and reversibly reduced the frequency of epileptiform bursting but did not change broad measures of network excitability or affect short-term synaptic facilitation. BICS01 was well tolerated following systemic injection at up to 1,000 mg/kg. However, we did not observe any protective effect of systemic BICS01 injection against acute seizures evoked by pentylenetetrazol. These results indicate that BICS01 is able to acutely reduce epileptiform activity in hippocampal networks. Further preclinical development studies to enhance pharmacokinetics and accumulation in the brain, as well as studies to understand the mechanism of action, are now required.

Automated summary

Drug-resistant epilepsy is still a major clinical and societal burden. This study evaluated the potential of BICS01, a synthetic compound, as a new anti-seizure drug. The results showed that BICS01 rapidly reduced the frequency of epileptiform bursting without affecting network excitability or short-term synaptic facilitation. It was well tolerated at high doses in animal models. However, it did not have a protective effect against acute seizures. Further studies are needed to improve its pharmacokinetics, brain accumulation, and understand its mechanism of action.