Staged anticonvulsant screening for chronic epilepsy

Area of Science:

• Neuroscience
• Pharmacology
• Epilepsy Research

Background:

• Current anticonvulsant drug discovery relies on models using induced seizures in normal animals.
• A significant portion of epilepsy patients (one-third) exhibit drug resistance to treatments identified through these conventional models.
• There is a critical need for novel screening strategies to identify effective anticonvulsants for treatment-resistant epilepsy.

Purpose of the Study:

• To evaluate a novel tiered screening program for anticonvulsant discovery.
• To investigate compounds using a model of chronic epilepsy with spontaneous seizures.
• To compare the efficacy of compounds identified through this tiered approach against traditional screening methods.

Main Methods:

• A tiered program was employed, starting with high-throughput in vitro models and progressing to low-throughput in vivo models.
• Organotypic hippocampal slice cultures were used to quantify epileptogenesis via lactate production and lactate dehydrogenase release.
• Compounds showing promise were further tested using in vitro electrophysiology and the kainate model of chronic epilepsy for spontaneous seizure analysis.

Main Results:

• The study screened 407 compound-concentration combinations.
• Celecoxib, a cyclooxygenase inhibitor, showed no effect on seizures in normal brain tissue models.
• Celecoxib demonstrated significant antiseizure activity across all tested models of chronic epilepsy.

Conclusions:

• Organotypic hippocampal cultures enable rapid screening of compounds in chronic epilepsy models by compressing the time scale of epileptogenesis.
• Biomarker assays for seizure-like activity and cell death in these cultures overcome throughput limitations of traditional in vivo models.
• This innovative screening strategy successfully identified an anticonvulsant (celecoxib) that traditional acute models would likely miss, offering a new avenue for drug discovery in resistant epilepsy.