Authors :
Presenting Author: Sheryl Anne D. Vermudez, PhD, BS – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S), La Jolla, CA, USA
Thomas Tolpiko, PhD – H. Lundbeck A/S, Copenhagen
Celina Zerbinatti, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Jesper Frank Bastlund, PhD – H. Lundbeck A/S, Copenhagen, Denmark
Marco Peters, PhD, MSc – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S), La Jolla, CA, USA
Rationale:
Patients with epilepsy, particularly those with developmental and epileptic encephalopathies (DEEs), are at risk for sudden unexpected death in epilepsy (SUDEP). Bexicaserin (LP352), a potent and highly selective 5-HT2C receptor superagonist, is an investigational drug currently in development for the treatment of seizures in patients with DEEs. We have previously demonstrated that by activating central 5-HT2C receptors, bexicaserin reduced seizures and respiratory arrest, a measurable correlate of SUDEP, in the DBA/1 mouse model of SUDEP. Here we utilized brain-wide imaging to measure c-Fos protein (a marker of brain activity) to characterize the brain circuits modulated by bexicaserin in the context of seizures and respiratory arrest in DBA/1 mice.
Methods:
Tone presentation to DBA/1 mice induced wild running, generalized tonic-clonic seizures, and respiratory arrest. Highly susceptible mice selected from a priming phase were orally administered vehicle or bexicaserin prior to testing (seizure chamber only [no tone] or with tone). Following testing, whole brains were dissected and cleared for brain-wide immunolabeling of the immediate early gene (IEG) c-Fos using iDISCO analysis. A separate cohort of mice were subjected to a similar protocol except that the mice remained in the homecage (ie, no chamber/tone presentation) after treatment.
Results:
A robust increase in whole-brain c-Fos levels—notably in regions involved in auditory processing, seizures, and respiratory control—was observed in vehicle-treated mice exposed to the tone stimulus compared with mice only exposed to the chamber, consistent with the expected behavioral phenotypes of seizures and respiratory arrest triggered by tone presentation. Remarkably, bexicaserin suppressed c-Fos expression in these regions for all mice treated, which corresponded with reductions in seizures and respiratory arrest. These effects of bexicaserin were not observed in basal conditions (ie, homecage environment), further suggesting that bexicaserin attenuates pathological brain activity linked to life-threatening epilepsy-associated conditions such as SUDEP.
Conclusions:
The efficacy of bexicaserin in reducing seizures and respiratory arrest in the DBA/1 mouse model of SUDEP is synonymous with its region-specific effects on brain activity. These data provide insights into the mechanisms underlying audiogenic seizures and seizure-induced respiratory arrest and the systems-level effects of bexicaserin resulting in reductions in seizures and SUDEP.
Funding:
This study was conducted by Porsolt (Le Genest-Saint-Isle, France) and Translucence Biosystems, Inc (Irvine, CA, USA) and sponsored by Longboard Pharmaceuticals (La Jolla, CA, USA; now a part of H. Lundbeck A/S).