In vitro seizure risk assessment using a microelectrode array and comparison with an in vivo rat study

Area of Science:

• Neuroscience
• Pharmacology
• Toxicology

Background:

• Drug-induced seizures are a significant clinical concern.
• Accurate seizure risk assessment is challenging in early drug development.
• Reliable in vitro assays are needed to predict in vivo convulsion potential.

Purpose of the Study:

• To evaluate the utility of in vitro microelectrode array (MEA) assays using rat primary neurons for predicting in vivo drug-induced convulsions.
• To compare MEA assay results with in vivo convulsion studies for fourteen known pro-convulsant drugs.

Main Methods:

• Established a stable in vitro culture of rat primary cortical neurons with balanced neuronal markers.
• Assessed electrophysiological changes using MEA, focusing on network burst frequency (NBF).
• Correlated in vitro NBF changes with in vivo convulsion data and measured drug concentrations in cerebrospinal fluid (CSF) via LC-MS/MS.

Main Results:

• The in vitro MEA assay demonstrated reproducible, concentration-dependent increases in NBF for several tested drugs.
• A specific NBF threshold was identified that could predict CSF drug concentrations associated with in vivo convulsions.
• The study validated the predictive capability of the MEA assay for drug-induced seizure risk.

Conclusions:

• In vitro MEA assays using rat primary neurons are a valuable tool for predicting in vivo convulsion risk.
• This assay can aid in early-stage drug screening and candidate selection by identifying potential pro-convulsant liabilities.
• The findings support the integration of MEA assays into preclinical drug development pipelines.